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Table Of Contents

Phenylalanine

Phenyalanine

Atom Symbol

MSDS

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Click on the image to go to the page which links to all the other pages on this web site on the subject of "oral chelation." The amino acids are the most important ingredients in an oral chelation formula. Phenylalanine is one of the important amino acids in the formula.

Menu Of Abstracts On Phenylalanine Click On The Number For The Abstract
...1...	White matter abnormalities in phenylketonuria: results of magnetic resonance measurements.	*Definition: Phenylketonuria (PKU)* means that the undigested amino acid, phenylalanine, is showing up in the urine**
...2...	Treatment of phenylalanine hydroxylase deficiency.	*Definition: Hydroxylase* means an enzyme**
...3...	Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.
...4...	MRI characterization of cerebral dysgenesis in maternal PKU.
...5...	Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia.
...6...	Gene therapy for phenylketonuria.
...7...	Science, medicine and phenylketonuria.
...8...	Possible neurologic effects of aspartame, a widely used food additive.
...9...	Mechanism of action of ochratoxin A.
...10...	Phenylketonuria: screening, treatment and maternal PKU.
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...11...	Maternal phenylketonuria: a metabolic teratogen.
...12...	Aspartame: review of recent experimental and observational data.
...13...	Maternal phenylketonuria. Review with emphasis on pathogenesis.
...14...	Aspartame intolerance.
...15...	Pharmacological effects of phenylalanine on seizure susceptibility: an overview.
...16...	Dietary treatment of destructive behavior associated with hyperphenylalaninemia.	*Definition: hyper* means too much, so hyperphenylalaninemia is too much phenylalanine. The ending, "mia," refers to the material being in the blood.**
...17...	Monoamine oxidase and catecholamine metabolism.
...18...	PKU in adolescents: rationale and psychosocial factors in diet continuation.
...19...	Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought.
...20...	Mutations in the phenylalanine hydroxylase gene: methods for their characterization.
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...21...	Population genetics of phenylketonuria.
...22...	The biochemistry and enzymology of amino acid dehydrogenases.
...23...	Protein metabolism in the cancer patient.
...24...	Hsp70s and lysosomal proteolysis.
...25...	The methotrexate story: a paradigm for development of cancer chemotherapeutic agents.
...26...	Dipeptidyl peptidase IV: development, design, synthesis and biological evaluation of inhibitors.
...27...	Dietary amino acids and brain function.
...28...	Long-term follow-up of children with classical phenylketonuria after diet discontinuation: a review.
...29...	Prevention of nephrotoxicity of ochratoxin A, a food contaminant.
...30...	The kinase-dependent function of Lck in T-cell activation requires an intact site for tyrosine autophosphorylation.
Menu Position 30
...31...	Diagnosis and management of tyrosinemia type I.
...32...	Phenylketonuria: contemporary screening and diagnosis.
...33...	Functions of the cystic fibrosis transmembrane conductance regulator protein.
...34...	Postinjury neutrophil priming and activation states: therapeutic challenges [editorial]
...35...	Phenylethylamine modulation of affect: therapeutic and diagnostic implications.
...36...	Painful keratoderma and photophobia: hallmarks of tyrosinemia type II.
...37...	Regulation of the activity of hepatic phenylalanine hydroxylase.
...38...	Formation, nutritional value, and safety of D-amino acids.
...39...	In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function.
...40...	Hydroxylation of salicylate and phenylalanine as assays for hydroxyl radicals: a cautionary note visited for the third time.
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...41...	The effects of high phenylalanine concentration on chick embryonic development.
...42...	Pteridines and mono-amines: relevance to neurological damage.
...43...	White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings.
...44...	Tetrahydrobiopterin deficiencies: preliminary analysis from an international survey.
...45...	Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia.
...46...	Nutritional therapy for selected inborn errors of metabolism.
...47...	Amino acid metabolism in uremia.
...48...	Use of cetirizine to investigate non-H1 effects of second-generation antihistamines.
...49...	Nurses' role in preventing birth defects in offspring of women with phenylketonuria [published erratum appears in J Obstet Gynecol Neonatal Nurs 1992 Sep-Oct;21(5):352]
...50...	Enzymology of the phenylalanine-hydroxylating system.
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...51...	Enzymatic catalysis by Friedel-Crafts-type reactions.
...52...	Transport of amino acids by the human placenta: predicted effects thereon of maternal hyperphenylalaninaemia.
...53...	The influence of mutations of enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency.
...54...	Gene therapy for phenylketonuria.
...55...	Relationship between genotype and phenotype in monogenic diseases: relevance to polygenic diseases.
...56...	Use of aspartame in pregnancy.
...57...	Defects of tetrahydrobiopterin synthesis and their possible relationship to a disorder of purine metabolism (the Lesch-Nyhan syndrome).
...58...	Dysfunction of CFTR bearing the delta F508 mutation.
...59...	The 'cerebral diabetes' paradigm for unipolar depression.
...60...	Congenital adrenal hyperplasia (CAH)--the place for prenatal treatment and neonatal screening.
Menu Position 60
...61...	Mechanical models of pseudopod formation.
...62...	The systemic administration of intravenous melphalan.
...63...	Trace amines and Tourette's syndrome.
...64...	Unraveling prion diseases through molecular genetics.
...65...	The control of aromatic amino acid catabolism and its relationship to neurotransmitter amine synthesis.
...66...	Cytosolic free Ca2+ signals in single adherent human neutrophils: generation and functional role.
...67...	Nutrition in the management of inborn errors of metabolism [published erratum appears in Clin Lab Med 1993 Dec;13(4):following table of contents]
...68...	Mutagenic activity of peptides and the artificial sweetener aspartame after nitrosation.
..69...	Inhibition of in vitro platelet aggregation and release and fibrinolysis.
...70...	Lysosomal degradation of microinjected proteins.
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...71...	Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. Medical Research Council Working Party on Phenylketonuria.
...72...	Clinical hyperthermia and chemotherapy.
...73...	Cystic fibrosis gene.
...74...	CFTR!
...75...	Guidelines for the treatment of vitiligo.
...76...	Immunonutrition: role of sulfur amino acids, related amino acids, and polyamines.
...77...	In vitro studies indicating antioxidative properties of rebamipide.
...78...	New perspectives and hope for cure-reflecting recent genetic developments in cystic fibrosis.
...79...	Illegitimate transcription: its use in the study of inherited disease.
...80...	Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.
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...81...	Artificial cells with emphasis on bioencapsulation in biotechnology.
...82...	Present status of boron neutron capture therapy.
...83...	Intestinal mucosal amino acid catabolism.
...84...	The clinical importance of hypochlorhydria (a consequence of chronic Helicobacter infection): its possible etiological role in mineral and amino acid malabsorption, depression, and other syndromes.
...85...	Entero-insular axis and diabetes mellitus.
...86...	Mechanisms by which cancer chemotherapeutic drugs induce emesis.
...87...	Therapeutic uses of microencapsulated genetically engineered cells.
...88...	A review of recent advances in understanding ochratoxicosis.
...89...	Molecular biology of Alzheimer's amyloid--Dutch variant.
...90....	Pharmacotherapy of attention-deficit/hyperactivity disorder in adults.
Menu Position 90
...91...	Treatment of osteoarthritis with aspartame.
...92...	Signal transduction in cells following binding of chemoattractants to membrane receptors.
...93...	Antioxidant potential of ferulic acid.
...94...	Copper, lysyl oxidase, and extracellular matrix protein cross-linking.
...95...	Strategies for correcting the delta F508 CFTR protein-folding defect.
...96...	A summary of mechanistic hypotheses of gabapentin pharmacology.
...97...	Amino acids for the measurement of protein synthesis in vivo by PET.
...98...	Amino acid metabolism in pediatric patients.
...99...	Scleroderma-like skin indurations in a child with phenylketonuria: a clinicopathologic correlation and review of the literature.
...100...	Protein turnover in the kidney and the whole body in humans.

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HealthGate Documents

Record 1 from database: MEDLINE
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Title: White matter abnormalities in phenylketonuria: results of magnetic resonance measurements.
Author: Ullrich K; Möller H; Weglage J; Schuierer G; Bick U; Ludolph A; Hahn Ullrich H; Fünders B; Koch HG
Address: Department of Paediatrics, University of MÂunster, Germany.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 78-82
Abstract: In adolescents and adults with PKU, blood phenylalanine levels above 10 mg/dl are generally associated with white matter changes in MRI. The grade of these changes is correlated to most recent blood phenylalanine levels. Based on studies using T2 relaxometry the MRI changes seem to be the consequence of a reversible dysmyelination. The clinical relevance of these white matter changes remains unclear as the extent of MRI alterations did not correlate with IQ, neurological and electrophysiological deficits of the patients. The intracerebral phenylalanine concentration as measured by protonspectroscopy amounts to about 50% of blood phenylalanine concentrations. Preliminary data indicate that brain phenylalanine levels remain constant if blood concentrations exceed 20 mg/dl. This might be of clinical relevance for the treatment of adolescent and adult PKU patients.
Language of Publication: English
Unique Identifier: 95284440

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MeSH Heading (Major): Brain Diseases|ET/*PA; Demyelinating Diseases|ET/*PA; Magnetic Resonance Imaging|*; Phenylketonuria|BL/*CO/DH
MeSH Heading: Brain Chemistry; Case-Control Studies; Electrophysiology; Human; Phenylalanine|AN

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 2 from database: MEDLINE
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Title: Treatment of phenylalanine hydroxylase deficiency.
Author: Smith I
Address: Medical Unit, Institute of Child Health, London, UK.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 60-5
Abstract: In phenylalanine hydroxylase deficiency detected by screening treatment in early life, both age at start of treatment and phenylalanine control during treatment are the major determinants of eventual psychological status. The influence of phenylalanine control declines with age but executive performance is influenced by hyperphenylalaninaemia at all ages. In a few subjects neurological deterioration has been reported years after relaxing or stopping treatment. MRI changes in brain white matter are present in most subjects no longer on a strict diet. These changes are usually reversible and closely related to phenylalanine status at the time of investigation. Whether or not the changes point to a specific vulnerability of white matter remains uncertain, although MRI changes were particularly prominent in subjects with neurological disability and may be irreversible in such subjects. Policies on treatment have to take account of these findings.
Language of Publication: English
Unique Identifier: 95284434

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MeSH Heading (Major): Phenylalanine Hydroxylase|*DF; Phenylketonuria|*DH/DI/EN
MeSH Heading: Adult; Age Factors; Child; Child, Preschool; Counseling; Decision Trees; Human; Infant, Newborn; Magnetic Resonance Imaging; Neonatal Screening; Patient Selection

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 3 from database: MEDLINE
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Title: Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.
Author: Lou HC
Address: John F Kennedy Institute, Glostrup, Denmark.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 86-8
Abstract: Phenylalanine and tyrosine constitute the two initial steps in the biosynthesis of dopamine, which, in its turn, is the metabolic precursor of noradrenaline and adrenaline. The extracellular phenylalanine concentration influences brain function in phenylalanine deficiency (PHD) by decreased dopamine synthesis. It has been shown to induce EEG slowing, and prolonged the performance time on neuropsychological tests. The tyrosine concentration in the CNS is reduced in PHD, possibly implying insufficient substrate (= tyrosine) for catecholamine synthesis due to competition inhibition, for instance across the blood brain barrier. In experimental studies it has been shown that the synthesis and release of dopamine can be influenced by an increase in the availability of tyrosine. In PHD an extra dietary intake of three doses of tyrosine (160 mg/kg/24h) induced a shortening of reaction time and decreased variability, and in a double-blind crossover study a similar dose has been reported to induce an improvement on psychological tests. In a study with lower doses of tyrosine (110 mg/kg/24 h) no effect was found on reaction time tests. These findings need to be substantiated, and more detailed information should be obtained.
Language of Publication: English
Unique Identifier: 95284442

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MeSH Heading (Major): Dopamine|*BI; Phenylalanine|*ME; Phenylketonuria|DH/*ME; Tyrosine|*ME/TU
MeSH Heading: Brain Chemistry; Clinical Trials; Cross-Over Studies; Double-Blind Method; Electroencephalography; Human; Neuropsychological Tests; Phenylalanine Hydroxylase|DF

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 4 from database: MEDLINE
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Title: MRI characterization of cerebral dysgenesis in maternal PKU.
Author: Allen RJ; Brunberg J; Schwartz E; Schaefer AM; Jackson G
Address: Division of Pediatric Neurology, University of Michigan Medical School, Ann Arbor, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 83-5
Abstract: MPKU pregnancies, with or without dietary treatment to reduce maternal plasma phenylalanine (phe), show variable, increased non-physiologic levels, as the putative cause of fetal teratogenicity. Cerebral dysgenesis with clinical neonatal microcephaly and congenital heart disease indicates altered organ morphogenesis. Although there is not an established precise relationship between maternal phe levels and outcome, dietary restriction before or early in gestation is universally advised. Both human experience and animal research have suggested differential organ responses to high and low phe levels. Structural microencephaly may be due to reduced brain volume or abnormal regional brain development. Infants in MPKU are also at risk to develop PKU. Microencephaly was evident by MRI in 8 of 21 infants born to 12 MPKU mothers; 2 infants of one mother developed PKU. All levels of gestational plasma phe were associated with otherwise structurally normal infant microencephalic brains appropriate for age in myelination. CHD occurred in one microencephalic infant of a classic MPKU treated in the first trimester. Maternal, cord and neonatal plasma phenylalanine at delivery did not correlate with teratogenic effects. Only untreated 'classic' MPKU fetal effects appear predictable.
Language of Publication: English
Unique Identifier: 95284441

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MeSH Heading (Major): Abnormalities, Multiple|*DI/ET; Brain|*AB; Magnetic Resonance Imaging|*; Microcephaly|*DI/ET; Phenylketonuria, Maternal|BL/*CO/DH
MeSH Heading: Female; Heart Defects, Congenital|DI; Human; Phenylalanine|BL; Pregnancy

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, MULTICASE
ISSN: 0803-5326
Country of Publication: NORWAY

Record 5 from database: MEDLINE
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Title: Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia.
Author: Güttler F; Guldberg P
Address: Danish Center for Human Genome Research, John F Kennedy Institute, Glostrup.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 49-56
Abstract: Phenylalanine hydroxylase (PAH) deficiency is a heterogeneous disease at the phenotype level. The spectrum of clinical and metabolic phenotypes spans from the potential pathogenic disease classical phenylketonuria (PKU) to the benign condition non-PKU hyperphenylalaninemia (non-PKU HPA). This review provides an introduction to the clinical variants of PAH deficiency, and summarizes our attempts to define the disease at the molecular level and to relate mutation genotype to clinical outcome. Complete genotype determination in a large number of patients with PAH-deficient hyperphenylalaninemia demonstrates that clinical heterogeneity can be explained by a multiplicity of mutations in the PAH gene. Some combinations of mutations are associated with phenylalanine levels fluctuating around the border between PKU and non-PKU HPA. However, certain mutations seem always to cause non-PKU HPA irrespective of the mutation on the second allele and can, therefore, unambiguously be designated as being associated with the non-PKU HPA phenotype. Our results suggest that mutation analysis in newborns presenting with hyperphenylalaninemia can be used for rapid and highly efficient differential diagnosis of PAH deficiency, and for predicting the severity of the disease. These possibilities may facilitate and optimize the management of hyperphenylalaninemia and thereby improve prognosis.
Language of Publication: English
Unique Identifier: 95284432

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MeSH Heading (Major): Mutation|*GE; Phenylalanine Hydroxylase|DF/*GE; Phenylketonuria|DI/EP/*GE/TH; Variation (Genetics)|*GE
MeSH Heading: Denmark|EP; Genotype; Human; Infant, Newborn; Phenotype; Phenylalanine|BL; Severity of Illness Index; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 6 from database: MEDLINE
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Title: Gene therapy for phenylketonuria.
Author: Eisensmith RC; Woo SL
Address: Department of Cell Biology, Baylor College of Medicine, Houston, TX.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 124-9
Abstract: Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). Three different vector systems have been developed to examine the potential of somatic gene therapy for the treatment of PKU. Recombinant retroviral vectors and DNA/protein complexes can efficiently transduce PAH-deficient hepatocytes in vitro, but their present application is limited by their low transduction efficiency in vivo. In contrast, infusion of a recombinant adenoviral vector expressing the human PAH cDNA into the portal circulation of PAH-deficient mice restores 10-80% of normal hepatic PAH activity and completely normalizes serum phenylalanine levels. At present, this effect is transient and re-administration has no further effect. However, this result suggests that PKU can be completely corrected by somatic gene therapy as more persistent vectors are developed.
Language of Publication: English
Unique Identifier: 95284421

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MeSH Heading (Major): Gene Therapy|*/MT; Phenylalanine Hydroxylase|*GE; Phenylketonuria|EN/GE/*TH
MeSH Heading: Animal; Disease Models, Animal; DNA, Complementary|GE; Gene Transfer; Human; Mice

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 7 from database: MEDLINE
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Title: Science, medicine and phenylketonuria.
Author: Scriver CR
Address: Department of Pediatrics, McGill University, Montreal, Canada.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 11-8
Abstract: Science addresses ignorance; medicine uses facts. The scientific approach to phenylketonuria (PKU) led to the discovery of its causes, both ultimate (allelic heterogeneity at the PAH locus) and proximate (dietary phenylalanine), the proximal phenotype (phenylalanine hydroxylase deficiency), the associated metabolic phenotype and the major distal phenotype (impaired cognitive development and neuropsychological function) for which the pathogenesis is still being investigated. By applying knowledge through newborn screening, early diagnosis and treatment, the brain disease of PKU has been greatly ameliorated. The population approach, which converted incidence into cases, revealed genetic heterogeneity in hyperphenylalaninemia involving four other loci, controlling cofactor (BH4) synthesis and recycling, and non-random geographic distribution of mutant PAH alleles of which more than 170 were known in April 1994. Various mechanisms including founder effect, genetic drift, hypermutability and selection (perhaps) explain the polymorphic aggregate frequency (approximately 0.01) and spectrum of PKU mutations in human populations.
Language of Publication: English
Unique Identifier: 95284417

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MeSH Heading (Major): Phenylketonuria|EP/*GE/ME/PC
MeSH Heading: Alleles; Gene Frequency; Genetic Screening; Human; Incidence; Infant, Newborn; Mutation|GE; Neonatal Screening; Phenotype; Polymorphism (Genetics); Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 8 from database: MEDLINE
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Title: Possible neurologic effects of aspartame, a widely used food additive.
Author: Maher TJ; Wurtman RJ
Address: Department of Pharmacology, Massachusetts College of Pharmacy, Boston 02115.
Source: Environ Health Perspect, 1987 Nov, 75:, 53-7
Abstract: The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research.
Language of Publication: English
Unique Identifier: 88082587

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MeSH Heading (Major): Aspartame|*AE/ME; Dipeptides|*AE; Food Additives|*AE; Seizures|*CI
MeSH Heading: Animal; Brain|DE/ME; Human; Phenylalanine|BL; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0091-6765
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Dipeptides); 0 (Food Additives); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine)

Record 9 from database: MEDLINE
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Title: Mechanism of action of ochratoxin A.
Author: Dirheimer G; Creppy EE
Address: Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Strasbourg, France.
Source: IARC Sci Publ, 1991, :115, 171-86
Abstract: Ochratoxin A has a number of toxic effects in mammals, the most notable of which is nephrotoxicity. It is also immunosuppressive, teratogenic and carcinogenic. The biochemical and molecular aspects of its action were first studied in bacteria. The appearance of 'magic spots' (ppGpp and pppGpp) pointed to inhibition of the charging of transfer ribonucleic acids (tRNA) with amino acids. This suggestion was confirmed by the demonstration that ochratoxin A inhibits bacterial, yeast and liver phenylalanyl-tRNA synthetases. The inhibition is competitive to phenylalanine and is reversed by an excess of this amino acid. As a consequence, protein synthesis is inhibited, as shown with hepatoma cells in culture, with Madin Darby canine kidney cells (which are much more sensitive) and in vivo in mouse liver, kidney and spleen, the inhibition being more effective in the latter two organs. An excess of phenylalanine also prevents inhibition of protein synthesis in cell cultures and in vivo. Analogues of ochratoxin A in which phenylalanine has been replaced by other amino acids have similar inhibitory effects on the respective amino acid-specific aminoacyl tRNA synthetases. 4R-Hydroxyochratoxin A, a metabolite of ochratoxin A, has a similar action, whereas ochratoxin alpha (the dihydroisocoumarin moiety) and ochratoxin B (ochratoxin A without chlorine) have no effect. Ochratoxin A might act on other enzymes that use phenylalanine as a substrate. We showed recently that it inhibits phenylalanine hydroxylase. In addition, the phenylalanine moiety of ochratoxin A is partially hydroxylated to tyrosine by incubation with hepatocytes and in vivo. This competitive action with phenylalanine might explain why this amino acid prevents the immuno-suppressive effect of ochratoxin A and partially prevents its teratogenic and nephrotoxic actions. The effect of ochratoxin A on protein synthesis is followed by an inhibition of RNA synthesis, which might affect proteins with a high turnover. Ochratoxin A also lowers the level of phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis; this inhibition is reported to be due to a specific degradation of mRNA that codes for this enzyme. Recently, ochratoxin A was also found to enhance lipid peroxidation both in vitro and in vivo. This inhibition might have an important effect on cell or mitochondrial membranes and be responsible for the effects on mitochondria that have been shown by several authors. Finally, the recent results of Pfohl-Leszkowicz et al. (this volume), who showed the formation of DNA adducts mainly in kidney but also in liver and spleen, explain the DNA single-strand breaks observed previously in mice and rats after acute and chronic treatment.
Language of Publication: English
Unique Identifier: 92316600

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MeSH Heading (Major): Ochratoxins|*PD/PK/TO; Phenylalanine|AA/*ME; Phenylalanyl T RNA Synthetase|*AI
MeSH Heading: Animal; Antibody Formation|DE; Bacteria|DE; Cells, Cultured; Dogs; DNA Damage; Eukaryotic Cells|DE; Guinea Pigs; Human; Kidney Tubules, Proximal|DE; Lipid Peroxidation|DE; Liver Neoplasms, Experimental|PA; Mice; Mice, Inbred BALB C; Mutagenicity Tests; Mycotoxicosis|ET; Phenylalanine Hydroxylase|AI; Phosphoenolpyruvate Carboxykinases|ME; Protein Synthesis Inhibitors|PD/TO; Rats; Structure-Activity Relationship; Support, Non-U.S. Gov't; Tumor Cells, Cultured|DE

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0300-5038
Country of Publication: FRANCE
CAS Registry/EC Number: EC 1.14.16.1 (Phenylalanine Hydroxylase); EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinases); EC 6.1.1.20 (Phenylalanyl T RNA Synthetase); 0 (Ochratoxins); 0 (Protein Synthesis Inhibitors); 303-47-9 (ochratoxin A); 3617-44-5 (Phenylalanine)

Record 10 from database: MEDLINE
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Title: Phenylketonuria: screening, treatment and maternal PKU.
Author: Matalon R; Michals K
Address: Research Institute, Miami Children's Hospital, FL 33155.
Source: Clin Biochem, 1991 Aug, 24:4, 337-42
Abstract: Phenylketonuria (PKU) has become a paradigm of a disease that can be identified by screening in the newborn period and treated to prevent serious complications. After many years of experience treating PKU, new challenges have emerged. It has become apparent that defective activity of phenylalanine hydroxylase leads to a spectrum of clinical presentations that has led to subclassifications of PKU. Blood phenylalanine greater than 1200 mumol/L usually indicates severe deficiency of phenylalanine hydroxylase and is often called "classical PKU." Blood phenylalanine levels between 600 and 1200 mumol/L lead to "atypical PKU." Cases where blood phenylalanine remains between 120 and 480 mumol/L on a normal diet are termed "benign hyperphenylalaninemia." A deficiency of the cofactor tetrahydrobiopterin (BH4), which is required for phenylalanine hydroxylase activity, leads to hyperphenylalaninemia. This cofactor is also required for the enzymatic hydroxylation of tyrosine and tryptophan. Cofactor defects account for only 1-3% of hyperphenylalaninemia, which has been termed "malignant PKU", but they must be identified so that appropriate treatment can be established. Long-term treatment of PKU is currently advised because loss of IQ, poor school performance, and behavior problems occur when blood phenylalanine levels increase. Therefore, there is reason to continue the diet as patients become older. When blood phenylalanine levels are elevated during pregnancy a "maternal PKU syndrome" may result. Babies born to untreated mothers with PKU are at risk for being small for gestational age with microcephaly, mental retardation and congenital heart defects. A national collaborative study for the treatment of maternal PKU is underway. The characterization of the gene for phenylalanine hydroxylase has added a new exciting chapter to the study of PKU.(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 92069901

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MeSH Heading (Major): Neonatal Screening|*; Phenylketonuria|*DI/GE/TH
MeSH Heading: Human; Infant, Newborn; Parents

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0009-9120
Country of Publication: CANADA

Record 11 from database: MEDLINE
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Title: Maternal phenylketonuria: a metabolic teratogen.
Author: Levy HL; Ghavami M
Address: Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Source: Teratology, 1996 Mar, 53:3, 176-84
Abstract: The maternal phenylketonuria (PKU) syndrome refers to the teratogenic effects of PKU during pregnancy. These effects include mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation. In untreated pregnancies wherein the mother has classic PKU with a blood phenylalanine level > or = 1,200 microM (20 mg/dl), the frequencies of these abnormalities in offspring are exceedingly high, approaching 75-90% for microcephaly and mental retardation and 15% for congenital heart disease. There is a dose response relationship with progressively lower frequencies of these abnormalities at lower phenylalanine levels, both in the pregnancies of women with variants of PKU and in treated classic PKU pregnancies. The pathogenesis of this syndrome is unknown; it may be related to inhibition by phenylalanine of large neutral amino acid transport across the placenta or to direct toxicity of phenylalanine and/or a phenylalanine metabolite in certain fetal organs. A mouse model for PKU now exists, and studies of maternal PKU in this model are in progress. The treatment of maternal PKU consists of biochemical control through a phenylalanine restricted diet during pregnancy. The best results are obtained with diet initiation before conception or no later than the earliest weeks of pregnancy. Women with PKU and their families require much psychosocial support to meet the strict requirements of a maternal PKU pregnancy, including compliance with a difficult diet. With such compliance, however, it seems that bearing normal or near normal offspring is possible.
Language of Publication: English
Unique Identifier: 96354349

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MeSH Heading (Major): Abnormalities, Multiple|*ET; Phenylketonuria|DI/*PC; Pregnancy Complications|DI/*PC
MeSH Heading: Alcoholism|DI; Animal; Diagnosis, Differential; Disease Models, Animal; Face|AB; Female; Fetal Alcohol Syndrome|DI; Fetal Growth Retardation|ET; Genetic Counseling; Heart Defects, Congenital|ET; Human; Infant; Infant, Newborn; Male; Mental Retardation|ET; Mice; Microcephaly|ET; Pregnancy; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0040-3709
Country of Publication: UNITED STATES

Record 12 from database: MEDLINE
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Title: Aspartame: review of recent experimental and observational data.
Author: Janssen PJ; van der Heijden CA
Address: National Institute of Public Health and Environmental Hygiene, Bilthoven, The Netherlands.
Source: Toxicology, 1988 Jun, 50:1, 1-26
Abstract: In this report the neurotoxicity of aspartame and its constituent amino acids aspartic acid and phenylalanine is reviewed. The adverse reactions ascribed to the consumption of aspartame-containing products, as reported in the U.S.A., are discussed and placed in perspective with the results of recent behavioural studies in humans and animals. The issue of common intake levels associated with proposed uses of aspartame is addressed. In brief, the following conclusions can be drawn: When aspartame is consumed at levels within the ADI-limit of 40 mg/kg body wt, there is no significant risk for an aspartate-induced neurotoxic effect in the brain. When aspartame is consumed at levels within the ADI-limit by normal subjects or persons heterozygous for phenylketonuria (PKU) the resultant plasma phenylalanine concentrations are practically always within the normal postprandial range; elevation to plasma concentrations commonly associated with adverse effects has not been observed. Persons suffering from phenylketonuria (PKU-homozygotes) on a phenylalanine-restricted diet should avoid consumption of aspartame. PKU-homozygotes on the (less strict) phenylalanine-liberalized diet should be made aware of the phenylalanine content of aspartame. In the available behavioural studies in humans with acute dosing, no adverse effects were observed. Long-term studies on behaviour and cognitive function in (sensitive) humans are lacking. Analyses of adverse reaction reports made by consumers in the U.S.A. have not yielded a specific constellation of symptoms clearly related to aspartame that would suggest a widespread public health hazard associated with aspartame use. Focussed clinical studies are now being carried out in the U.S.A.; the results should provide additional evidence concerning the interpretation of the reports on adverse reactions ascribed to aspartame. In the regulation of admitted uses for aspartame the possibility of intake levels exceeding the ADI-limit in some groups of consumers should be a point of attention.
Language of Publication: English
Unique Identifier: 88265115

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MeSH Heading (Major): Aspartame|*AE/ME/TO; Dipeptides|*AE; Phenylalanine|BL/*ME
MeSH Heading: Animal; Behavior, Animal|DE; Brain Chemistry|DE; Human; Phenylketonuria|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0300-483X
Country of Publication: NETHERLANDS
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine)

Record 13 from database: MEDLINE
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Title: Maternal phenylketonuria. Review with emphasis on pathogenesis.
Author: Levy HL
Address: Children's Hospital, Boston, Mass.
Source: Enzyme, 1987, 38:1-4, 312-20
Abstract: Maternal phenylketonuria (PKU) refers to fetal damage from PKU in the pregnant woman. The progeny from such pregnancies are almost always microcephalic and mentally subnormal and have an increased frequency of congenital heart disease and low birth weight. Treatment with a phenylalanine-restricted diet, if begun before conception, seems to protect the fetus. The degree of protection is much less if dietary treatment is delayed until the pregnancy is in progress. The origin of fetal damage in maternal PKU is not known. Due to placental concentration of amino acids, the fetus is exposed to a higher concentration of phenylalanine than that in the mother, but it is not certain that phenylalanine is the toxic agent. Animal models made hyperphenylalaninemic by the administration of phenylalanine, often accompanied by a phenylalanine hydroxylase inhibitor, do not reproduce the full maternal PKU syndrome; but fetuses and newborns from these models have had reduced growth of the body and brain, and offspring later may show evidence of impaired learning ability.
Language of Publication: English
Unique Identifier: 88151861

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MeSH Heading (Major): Abnormalities, Multiple|*ET; Phenylketonuria|*CO/DH/PX; Pregnancy Complications|*DH/PX
MeSH Heading: Animal; Female; Human; Mental Retardation|ET; Pregnancy

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0013-9432
Country of Publication: SWITZERLAND

Record 14 from database: MEDLINE
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Title: Aspartame intolerance.
Author: Garriga MM; Metcalfe DD
Address: Mast Cell Physiology Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Source: Ann Allergy, 1988 Dec, 61:6 Pt 2, 63-9
Abstract: Aspartame is a food additive marketed under the brand name Nutrasweet. Aspartame is a white, odorless, crystalline powder and consists of two amino acids, L-aspartic acid and L-phenylalanine. It is 180 times as sweet as sugar. The Food and Drug Administration (FDA) first allowed its use in dry foods in July 1981 and then approved its use in carbonated beverages in July 1983. It has subsequently been approved for use in a number of materials including multivitamins, fruit juices, stick-type confections, breath mints, and iced tea. The FDA requires the statement "phenylketonurics: contains phenylalanine" on labels of food products containing aspartame because individuals with phenylketonuria (PKU) must restrict their intake of phenylalanine. Aspartame is judged to be free of long-term cancer risks. Aspartame is not stable under certain conditions including baking and cooking, and prolonged exposure to acid conditions. In such situations it loses its sweetness. Products formed from aspartame include its component amino acids (phenylalanine and aspartic acid), methanol, and diketopiperazine (DKP). Animal studies show DKP to be nontoxic. Methanol occurs in small amounts and does not exceed that formed during consumption of many foods including fresh fruits and vegetables. FDA's Center for Food Safety and Applied Nutrition (CFSAN) monitors aspartame's safety in part through reports of adverse reactions. After aspartame was approved for use in carbonated beverages, the FDA received an increased number of reports concerning adverse reactions related to aspartame. The Centers for Disease Control (CDC) reviewed these reports, which included complaints of neurologic, gastrointestinal, andallergic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 89086740

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MeSH Heading (Major): Aspartame|*AE; Dipeptides|*AE; Product Surveillance, Postmarketing|*
MeSH Heading: Behavior; Female; Headache|ET; Human; Hypersensitivity|ET; Male

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0003-4738
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame)

Record 15 from database: MEDLINE
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Title: Pharmacological effects of phenylalanine on seizure susceptibility: an overview.
Author: Sze PY
Address: Department of Pharmacology, Chicago Medical School, Illinois 60064.
Source: Neurochem Res, 1989 Feb, 14:2, 103-11
Abstract: The effects of excessive doses of phenylalanine on seizure susceptibility were examined in animal models in the past, primarily because of their relevance to phenylketonuria. It was thought that such effects might involve brain monoaminergic mechanisms. Recently, this issue has been pursued with a renewed interest but for a different reason. The dipeptide sweetener, aspartame, contains a phenylalanine residue. In the last three years, a number of studies involving as many as nine animal models of seizures have reexamined the effects of phenylalanine (and aspartame) on seizure thresholds. Data from these studies are in general agreement that aspartame at dosage levels below 1,000 mg/kg, or phenylalanine at equimolar doses, is without an effect on seizure susceptibility in animals. When the dosage level of aspartame reaches 1,000 mg/kg, the findings between various laboratories and from different animal models of seizures are inconsistent, showing either no effect or a proconvulsant effect. The Acceptable Daily Intake of aspartame in humans set by the Food and Drug Administration is 50 mg/kg/day. Thus, the data from the excessive bolus doses in rodents do not appear to be relevant to human use. This article provides a detailed review of the data from both early and recent studies and points out the methodological problems apparent at such high doses.
Language of Publication: English
Unique Identifier: 89262433

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MeSH Heading (Major): Aspartame|*PD; Dipeptides|*PD; Phenylalanine|*TO; Seizures|CI/*PP
MeSH Heading: Animal; Disease Models, Animal; Disease Susceptibility; Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0364-3190
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine)

Record 16 from database: MEDLINE
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Title: Dietary treatment of destructive behavior associated with hyperphenylalaninemia.
Author: Baumeister AA; Baumeister AA
Address: Department of Psychology, Louisiana State University, Baton Rouge 70803, USA.
Source: Clin Neuropharmacol, 1998 Jan, 21:1, 18-27
Abstract: Behavior disorders frequently are associated with mental retardation. The most common interventions involve psychotropics, behavior modification, or both. Etiologically based treatments, derived from an understanding of underlying disease pathogeneses, are infrequent. However, several genetic diseases are associated with elevated rates of destructive responding. The hyperphenylalaninemias provide an excellent model for alternative interventions that have clear biological plausibility. A literature review is undertaken that provides the biochemical rationale for treatment with a low-phenylalanine diet. Several phenylalanine dietary control studies designed to manage aberrant responding among patients with hyperphenylalaninemia are summarized. Together they provide strong evidence that dietary phenylalanine restriction is the treatment of choice among patients ranging from classic phenylketonuria to milder hyperphenylalaninemia. Corroborating evidence derived from phenylalanine loading, magnetic resonance imaging, and dietary amino acid supplementation studies is presented.
Language of Publication: English
Unique Identifier: 98240444

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|*DT/*PX; Mental Disorders|*DH/*PX; Mental Retardation|*PX; Phenylalanine|*ME
MeSH Heading: Adult; Case Report; Female; Human; Male; Middle Age; Phenylketonuria|DH/PX

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0362-5664
Country of Publication: UNITED STATES

Record 17 from database: MEDLINE
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Title: Monoamine oxidase and catecholamine metabolism.
Author: Kopin IJ
Address: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Source: J Neural Transm Suppl, 1994, 41:, 57-67
Abstract: The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase (Hare, 1928). Almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme. Zeller (1938) distinguished monoamine oxidase as different from several other amine oxidases, such as diamine oxidase. Although it was generally assumed that catecholamines were metabolized by MAO, this was not established until isotopically labelled epinephrine and an MAO inhibitor became available. Schayer (1951) found that after administration of N-methyl-14C-epinephrine, only about 50% of the radioactivity appeared in the urine, whereas when the 14C label was incorporated into the beta-position on the side chain, almost all of the radioactivity could be recovered. One year later, Zeller et al. (1952) discovered that isonicotinic acid hydrazide (iproniazid) inhibited MAO. When animals pretreated with the MAO inhibitor were administered N-methyl-14C-epinephrine, almost all of the radioactivity was recovered (Schayer et al., 1955), indicating that the enzyme was responsible for the metabolism of about half of the administered catecholamine. Schayer et al. (1952, 1953) had found that five urinary metabolite products of beta-labelled-14C-norepinephrine could be separated by paper chromatography, but the chemical structures of these compounds were not known. Armstrong et al. (1957) showed that 3-methoxy-4-hydroxymandelic acid (vanillyl mandelic acid, VMA) was the major metabolite of norepinephrine and Shaw et al. (1957) demonstrated that large amounts of homovanillic acid (HVA) were excreted in urine after administration of 3,4-dihydroxy-phenylalanine (DOPA). These observations led Axelrod to examine the possibility that O-methylation might precede deamination and to his discovery of catechol-O-methyl transferase (Axelrod, 1957, 1959). At that time it became apparent that there were two possible routes for metabolism of norepinephrine to VMA--either deamination followed by O-methylation or O-methylation and subsequent deamination. The relative roles of these two pathways in terminating the physiological actions of catecholamines then became a focus of attention. Biochemical methods were used to access directly the relative importance of the two metabolic pathways. Physiological methods, based on the effects of drugs which alter metabolism of the catecholamine, were used to examine the role of MAO and COMT in terminating the actions of administered or endogenously released catecholamines.
Language of Publication: English
Unique Identifier: 95016639

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MeSH Heading (Major): Catecholamines|*ME; Monoamine Oxidase|*PH
MeSH Heading: Animal; Catechol O-Methyltransferase|PH; Human; Isoenzymes|PH; Monoamine Oxidase Inhibitors|TU; Parkinson Disease|DT; Selegiline|TU

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0303-6995
Country of Publication: AUSTRIA

Record 18 from database: MEDLINE
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Title: PKU in adolescents: rationale and psychosocial factors in diet continuation.
Author: Levy HL; Waisbren SE
Address: Biochemical Genetics Unit of the Division of Genetics, Children's Hospital, Boston, MA 02115, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 92-7
Abstract: Follow-up of early-treated children with PKU has shown that diet discontinuation in childhood presents risks of cognitive and emotional dysfunction in a substantial number of adolescents and young adults. This dysfunction includes IQ loss, mental processing abnormalities, learning difficulties, anxiety and personality disorders. In addition, neurologic deterioration has been reported in several such individuals. As a consequence of this current understanding of PKU, diet continuation, at least through adolescence and in the young adult years, is now recommended. Many centers are extending this to a policy of "diet for life". This represents a major challenge to adolescents and their families. Metabolic control using the criteria applied during childhood is virtually impossible to achieve past 12 years of age. Time constraints, social pressures, financial limitations and growing independence from the family combine to interfere with dietary control. Added to these difficulties are the biological changes during teenage years which reduce phenylalanine tolerance. To meet these challenges, we have identified a number of psychosocial factors that interfere with adherence to medical recommendations. The factors most highly related to metabolic control were social support for the diet and positive perceptions of treatment. This information has led to the development of support programs for adolescents and young adults with PKU.(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 95284444

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MeSH Heading (Major): Adolescent Psychology|*; Cognition Disorders|*ET; Mental Disorders|*ET; Phenylketonuria|CO/*DH/ME/*PX
MeSH Heading: Adolescence; Attitude to Health; Follow-Up Studies; Human; Patient Compliance; Patient Education; Self-Help Groups; Social Support; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 19 from database: MEDLINE
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Title: Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought.
Author: Diamond A
Address: Department of Psychology, University of Pennsylvania, Philadelphia 19104-6196, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 89-91
Abstract: Results of a longitudinal study of children treated early and continuously for phenylketonuria (PKU) indicated that those children whose plasma phenylalanine (Phe) levels were approximately 3-5 times normal (6-10 mg/dl; levels previously considered safe in the US) were impaired in cognitive functions dependent on prefrontal cortex. In particular, the children had difficulty when required to hold information in the mind and, at the same time, exercise inhibitory control to resist doing what might be their first inclination. The deficits were evident in relation to each of several comparison groups and at all three age ranges (infants, toddlers and young children). The deficits appeared to be selective in that the same children who were impaired on the prefrontal cortex tests performed normally on the control tests. Since most of the control tasks tap functions dependent on parietal cortex or the medial temporal lobe, these results suggest that those functions are spared. To investigate the biological mechanism causing these cognitive deficits, we created an animal model of early-treated PKU. The results indicated that rats whose plasma Phe levels were mildly, but chronically, elevated had cognitive deficits (impaired performance on a behavioral task dependent on frontal cortex (delayed alternation)) and neurochemical changes (most notably, reduced dopamine metabolism in frontal cortex).
Language of Publication: English
Unique Identifier: 95284443

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MeSH Heading (Major): Cognition Disorders|BL/*ET/PP; Phenylalanine|*BL; Phenylketonuria|*BL/CO/DH
MeSH Heading: Animal; Case-Control Studies; Cerebral Cortex|PP; Contrast Sensitivity; Cross-Sectional Studies; Disease Models, Animal; Human; Longitudinal Studies; Rats

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 20 from database: MEDLINE
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Title: Mutations in the phenylalanine hydroxylase gene: methods for their characterization.
Author: Guldberg P; Güttler F
Address: Danish Center for Human Genome Research, John F Kennedy Institute, Glostrup.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 27-33
Abstract: Mutations in the phenylalanine hydroxylase (PAH) gene represent the root cause of PAH-deficient hyperphenylalaninemia. To date, more than 160 different mutations have been reported. Single-base substitutions and microdeletions account for the majority of molecular defects. This review provides a brief general introduction to various strategies for detection of PAH mutations, and summarizes our own methodological developments. We have established a method based on PCR in combination with denaturing gradient gel electrophoresis (DGGE) for mutation scanning of the entire coding sequence and all exon/intron boundaries of the PAH. Systematic application of this method to the study of a large number of mutant chromosomes from hyperphenylalaninemic patients demonstrated a 98% diagnostic efficiency and a 100% mutation detection efficiency. We have created compromised PCR and DGGE conditions for simultaneous amplification and simultaneous mutation scanning of all PAH-coding fragments. This technique is convenient in a diagnostic setting and allows "same-day" DNA-based diagnosis of newborns with hyperphenylalaninemia. A further modification of the method allows unambiguous identification of known mutations, circumventing the cumbersome step of nucleotide sequencing.
Language of Publication: English
Unique Identifier: 95284423

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MeSH Heading (Major): Mutation|*GE; Phenylalanine Hydroxylase|DF/*GE; Phenylketonuria|DI/*GE
MeSH Heading: DNA Mutational Analysis; Electrophoresis, Polyacrylamide Gel|MT; Genetic Screening|MT; Human; Infant, Newborn; Neonatal Screening|MT; Polymerase Chain Reaction|MT; Sensitivity and Specificity; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 21 from database: MEDLINE
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Title: Population genetics of phenylketonuria.
Author: Eisensmith RC; Woo SL
Address: Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 19-26
Abstract: Phenylketonuria (PKU) is an autosomal recessive disorder caused by a large number of mutations at the phenylalanine hydroxylase (PAH) locus, most of which are strongly associated with specific RFLP or VNTR haplotypes. One of the major questions remaining in PKU research is why this apparently maladaptive disorder has been maintained at a frequency of approximately 1 in 10,000 among Caucasians. A growing number of studies have provided evidence that both the relatively high frequency of PKU and the strong mutation/haplotype associations might reflect the existence of multiple founding populations for PKU. Examples of putative founding populations for PKU in both Europe and Asia will be presented. Some PAH mutations are associated with multiple haplotypes, suggesting recurrence. Evidence for and against recurrence as the mechanism responsible for the association of the R408W mutation with RFLP haplotypes 1 and 2 will be discussed.
Language of Publication: English
Unique Identifier: 95284422

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MeSH Heading (Major): Founder Effect|*; Gene Frequency|*GE; Mutation|*GE; Phenylketonuria|*EP/*GE
MeSH Heading: Asia|EP; Epidemiology, Molecular; Europe|EP; Haplotypes|GE; Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 22 from database: MEDLINE
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Title: The biochemistry and enzymology of amino acid dehydrogenases.
Author: Brunhuber NM; Blanchard JS
Address: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
Source: Crit Rev Biochem Mol Biol, 1994, 29:6, 415-67
Abstract: This review is an exhaustive description of the biochemistry and enzymology of all 17 known NAD(P)(+)-amino acid dehydrogenases. These enzymes catalyze the oxidative deamination of an amino acid to its keto acid and ammonia, with the concomitant reduction of either NAD+ or NADP+. These enzymes have many important applications in industrial and medical settings and have been the object of prodigious enzymological research. This article describes all that is known about the poorly characterized members of the family and contains detailed information on the better characterized enzymes, including valine, phenylalanine, leucine, alanine, and glutamate dehydrogenases. The latter three enzymes have been the subject of extensive enzymological experimentation, and, consequently, their chemical mechanisms are discussed. The three-dimensional structure of the Clostridium symbiosum glutamate dehydrogenase has been determined recently and remains the only structure known of any amino acid dehydrogenase. The three-dimensional structure and its implications to the chemical mechanisms and rate-limiting steps of the amino acid dehydrogenase family are discussed.
Language of Publication: English
Unique Identifier: 95220046

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MeSH Heading (Major): Amino Acid Oxidoreductases|*CH/*ME
MeSH Heading: Animal; Human; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1040-9238
Country of Publication: UNITED STATES

Record 23 from database: MEDLINE
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Title: Protein metabolism in the cancer patient.
Author: Garlick PJ; McNurlan MA
Address: Department of Surgery, State University of New York, Health Sciences Center, Stony Brook 11794-8191, USA.
Source: Biochimie, 1994, 76:8, 713-7
Abstract: The 'flooding' method has been widely used for measuring protein synthesis in animal tissues in vivo and in vitro, employing radioactively labelled amino acids, because it minimises errors in determining the specific radioactivity of the direct precursor of protein synthesis. This approach has now been modified for measuring protein synthesis rates in tumours and healthy tissues of humans by injection of the stable isotopic labels, [1(-13)C]leucine or [2H5]phenylalanine, followed by tissue sampling during surgery. Based on the observation that rates of protein synthesis correlate with changes in the expression of cell proliferation markers, we have suggested that changes in protein synthesis in tumours can be used as indices of changes in tumour growth. Measurements in colorectal cancer patients have shown that protein synthesis is stimulated 80% by feeding, suggesting that the tumour is not a pure parasite, but responds to exogenous nutrients. Moreover, when the composition of the amino acids given to the patient was changed from a balanced mixture to one supplemented with branched chain amino acids, the response of the tumour to feeding was significantly diminished, suggesting that tumour growth might be modulated by diet composition. Dietary supplements of arginine have been shown previously to inhibit tumour growth in animals, probably by activating the immune system. However, in breast cancer patients arginine stimulated tumour protein synthesis, suggesting that arginine might have separate stimulatory effects on the tumour and the immune system, the outcome depending on which effect predominates.
Language of Publication: English
Unique Identifier: 95201034

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MeSH Heading (Major): Neoplasms|DH/*ME; Proteins|*BI
MeSH Heading: Amino Acids, Branched-Chain|AD/ME; Animal; Arginine|AD/ME; Carbon Isotopes; Deuterium; Fasting; Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0300-9084
Country of Publication: FRANCE

Record 24 from database: MEDLINE
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Title: Hsp70s and lysosomal proteolysis.
Author: Terlecky SR
Address: Department of Biology, University of California, San Diego, La Jolla 92093-0322.
Source: Experientia, 1994 Nov, 50:11-12, 1021-5
Abstract: Confluent cultured cells activate a lysosomal pathway of polypeptide breakdown in response to withdrawal of serum growth factors. The substrates for this proteolytic pathway are a restricted class of cytosolic polypeptides containing peptide sequences biochemically related to lysine-phenylalanine-glutamate-arginine-glutamine, or, in single amino acid abbreviations, KFERQ. The heat shock cognate protein of 73 kD (hsc73) binds to a variety of polypeptides via this molecular determinant and facilitates their lysosomal import and degradation. In addition, a portion of intracellular hsc73 resides within the lysosome and appears to be an essential component of the proteolytic machinery. Several potential mechanisms by which hsc73 mediates selective lysosomal import and degradation of polypeptides are discussed.
Language of Publication: English
Unique Identifier: 95080363

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MeSH Heading (Major): Heat-Shock Proteins 70|*PH; Lysosomes|*ME; Proteins|*ME
MeSH Heading: Amino Acid Sequence; Animal; Biological Transport; Human; Molecular Sequence Data; Oligopeptides|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0014-4754
Country of Publication: SWITZERLAND

Record 25 from database: MEDLINE
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Title: The methotrexate story: a paradigm for development of cancer chemotherapeutic agents.
Author: Huennekens FM
Address: Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037.
Source: Adv Enzyme Regul, 1994, 34:, 397-419
Abstract: Methotrexate (MTX), one of the earliest cancer chemotherapy agents, continues to be used extensively in the treatment of leukemia and a variety of other tumors. The efficacy of this drug results from its facile uptake by cells, rapid polyglutamylation and virtually stoichiometric inhibition of dihydrofolate reductase (DHFR), a key enzyme in cell replication. From the work of a multitude of biochemists, molecular biologists, organic chemists and pharmacologists, much is known about the mode of action of MTX and the mechanisms by which tumors exhibit inherent or acquired resistance to this drug. MTX enters cells primarily by a carrier-mediated active transport system whose principal substrate is 5-methyltetrahydrofolate, and additional glutamates are added to the gamma-position of the parent glutamate moiety. The tight binding of MTX to DHFR is defined from NMR and X-ray crystallographic studies of the enzyme and its drug or substrate complexes, supplemented by site-directed mutagenesis to confirm specific interactions. Resistance to the drug, encountered in cell culture model systems or in cancer patients, can result from an increased level of DHFR (due to gene amplification), mutant DHFR with reduced affinity for MTX, or decreased uptake or polyglutamylation of the drug. Although DHFR is an extremely well-studied enzyme, there is still some uncertainty about its kinetics, mechanism for reduction of folate, multiple forms, and activation by a diverse group of agents. Prodrug forms of MTX, e.g., MTX alpha-phenylalanine, which can be activated by carboxypeptidase A-monoclonal antibody conjugates, offer promise for improved efficacy of the drug by selective targeting to tumors. The large body of information summarized above has aided in the development of other folate antagonists, provides a paradigm for assessing the status of other cancer chemotherapeutic agents in current use, and offers a platform from which to speculate about the future of the field.
Language of Publication: English
Unique Identifier: 95028763

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MeSH Heading (Major): Antimetabolites, Antineoplastic|*PD/TU; Methotrexate|AA/ME/*PD/TU; Neoplasms|*DT; Tetrahydrofolate Dehydrogenase|*AI
MeSH Heading: Drug Resistance; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0065-2571
Country of Publication: ENGLAND

Record 26 from database: MEDLINE
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Title: Dipeptidyl peptidase IV: development, design, synthesis and biological evaluation of inhibitors.
Author: Borloo M; De Meester I
Address: Universitaire Instelling Antwerpen, Departement Farmaceutische Wetenschappen, Wilrijk, BelgiÂe.
Source: Verh K Acad Geneeskd Belg, 1994, 56:1, 57-88
Abstract: Dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5) is a highly specific serine protease which cleaves off N-terminal dipeptides from peptides with a penultimate proline or alanine. The enzyme is widely distributed in mammalian cells and tissues, but specific activities differ greatly. In the hematopoietic system it is found almost exclusively on T cells, where it is identified as CD26, a T cell activation molecule. DPP IV may be involved in the metabolism of peptides, intestinal assimilation and cell adhesion and it plays an integral role in T cell activation. DPP IV inhibitors may provide help during the further elucidation of the biological function(s) of this enzyme. Moreover, because of the integral role the enzyme plays in T cell activation, specific inhibition of DPP IV may constitute a new way of immune modulation. N-Peptidyl-O-acylhydroxylamines and boronic acid analogues of proline and alanine are two known DPP IV inhibitors. The major drawbacks for their therapeutic use are for the hydroxylamines, the toxicity and for the boronic acid derivatives, the chemical liability. A low toxicity, acceptable stability and a high specificity are essential criteria for the design of inhibitors that are suitable, not only for experimental, but also for therapeutic use. Therefore we proposed 5 types of potential DPP IV inhibitors: azapeptides, azetidines, Michael substrates, reduced peptides and phosphonic acids. All the synthesized compounds possess a substrate-like structure, which is a pre-requisite for recognition by the enzyme. We choose for a modified proline or alanine at the penultimate position, substituted with glycine, alanine, valine, isoleucine or phenylalanine at the N-terminus. The prepared compounds were screened biologically at a 5 mM concentration with a fluorometric method using Gly-Pro-4-Me-2NA as substrate.
Language of Publication: English
Unique Identifier: 94270022

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MeSH Heading (Major): Dipeptidyl Peptidases|AI/*CS/PD
MeSH Heading: Aza Compounds|CS; Azetidines|CS; Human; Phosphonic Acids|CS; Substrate Specificity

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0372-610X
Country of Publication: BELGIUM

Record 27 from database: MEDLINE
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Title: Dietary amino acids and brain function.
Author: Fernstrom JD
Address: University of Pittsburgh School of Medicine, PA 15213.
Source: J Am Diet Assoc, 1994 Jan, 94:1, 71-7
Abstract: Two groups of amino acids--the aromatic and the acidic amino acids--are reputed to influence brain function when their ingestion in food changes the levels of these amino acids in the brain. The aromatic amino acids (tryptophan, tyrosine, phenylalanine) are the biosynthetic precursors for the neurotransmitters serotonin, dopamine, and norepinephrine. Single meals, depending on their protein content, can rapidly influence uptake of aromatic amino acid into the brain and, as a result, directly modify their conversion to neurotransmitters. Such alterations in the production of transmitters can directly modify their release from neurons and, thus, influence brain function. The acidic amino acids glutamate and aspartate are themselves brain neurotransmitters. However, they do not have ready access to the brain from the circulation or the diet. As a result, the ingestion of proteins, which are naturally rich in aspartate and glutamate, has no effect on the level of acidic amino acid in the brain (or, thus, on brain function by this mechanism). Nevertheless, the food additives monosodium glutamate and aspartame (which contains aspartate) have been reputed to raise the level of acidic amino acid in the brain (when ingested in enormous amounts), to modify brain function, and even to cause neuronal damage. Despite such claims, a substantial body of published evidence clearly indicates that the brain is not affected by ingestion of aspartame and is affected by glutamate only when the amino acid is administered alone in extremely large doses. Therefore, when consumed in the diet neither compound presents a risk to normal brain function.
Language of Publication: English
Unique Identifier: 94095800

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MeSH Heading (Major): Amino Acids|*AD/ME; Brain|*PH; Neurotransmitters|*BI
MeSH Heading: Affect; Animal; Cholesterol|BL; Dietary Carbohydrates|ME; Dietary Fats|ME; Dietary Proteins|ME; Human; Serotonin|BI/PH

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0002-8223
Country of Publication: UNITED STATES

Record 28 from database: MEDLINE
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Title: Long-term follow-up of children with classical phenylketonuria after diet discontinuation: a review.
Author: Potocnik U; Widhalm K
Address: Department of Pediatrics, University of Vienna, Austria.
Source: J Am Coll Nutr, 1994 Jun, 13:3, 232-6
Abstract: The age at which children suffering from classical phenylketonuria can safely discontinue their dietary therapy has been constantly disputed over the past decades. Recently, most phenylketonuria centers have begun to recommend a life-long diet, especially for female patients. Male patients are also advised to continue their diet until at least well into adult age. As a result of this new outlook in therapy management, we reviewed the existing literature and summarized all relevant long-term follow-up data of children who discontinued their debts at an early age, focusing on intellectual and neurological performance. The abilities of these children are compared during dietary treatment and again several years after diet discontinuation. Results show clearly that children maintaining their diets into their teens have fewer deficits than do those terminating their diets before 10 years of age. It seems essential to initiate diet early, and to keep blood phenylalanine levels < 600 mumol/L and well controlled to at least age 10 to ensure satisfactory long-term development of the patient. Furthermore, it seems highly justified to maintain a life-long diet which can be liberalized, but not completely discontinued in adulthood.
Language of Publication: English
Unique Identifier: 94358313

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MeSH Heading (Major): Phenylketonuria|*DH/PP/PX
MeSH Heading: Adolescence; Child; Child, Preschool; Female; Follow-Up Studies; Human; Infant; Infant, Newborn; Intelligence; Longitudinal Studies; Male; Nervous System|PP; Phenylalanine|BL

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0731-5724
Country of Publication: UNITED STATES

Record 29 from database: MEDLINE
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Title: Prevention of nephrotoxicity of ochratoxin A, a food contaminant.
Author: Creppy EE; Baudrimont I; Betbeder AM
Address: Toxicology Department, University of Bordeaux, France.
Source: Toxicol Lett, 1995 Dec, 82-83:, 869-77
Abstract: Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, mainly by Aspergillus ochraceus and also by Penicilium verrucosum. It was found all over the world in feed and human food and blood as well as in animal blood and tissues. The most threatening effects of OTA are its nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotoxic to all animal species studied so far and is increasingly involved in the Balkan endemic nephropathy (BEN), a human chronic interstitial nephropathy which is most of the time associated to urinary tract tumours. Since it seems impossible to avoid contamination of foodstuffs by toxigenic fungi, detoxification and detoxication for OTA are needed. To reduce or abolish the OTA-induced toxic effects, several mechanisms were investigated. The results of these investigations showed that some of the potential antidotes were efficient in preventing the main OTA toxic effects whereas some others were not. Promising compounds are structural analogues of OTA, and/or compounds having a high binding affinity for plasma proteins such as piroxicam, a non-steroidal anti-inflammatory drug (NSAID). Some enzymes such as superoxide dismutase (SOD) and catalase, radical scavengers, vitamins, prostaglandin (PG) synthesis inhibitors, (such as piroxicam), pH modificators, adsorbant resin such as cholestyramine etc. are efficient in vivo. Some of the results obtained in vivo were already confirmed in vitro and gave useful information on how to safely use these antidotes. The most generally acting compound seems to be A19 (Aspartame), a structural analogue of OTA and phenylalanine. When given to rats A19 (25 mg/kg/48 h) combined to OTA (289 micrograms/kg/48 h) for several weeks largely prevented OTA nephrotoxicity and genotoxicity. When given after intoxication of animals with OTA it washes out the toxin efficiently from the body. In vitro, A19 (10 micrograms/ml) prevents OTA (20-500 micrograms/ml) binding to plasma proteins. Its general action without any known side effect in humans and in animals, points at A19 to be the best candidate for preventing the OTA-induced subchronic effects.
Language of Publication: English
Unique Identifier: 96170186

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MeSH Heading (Major): Aspartame|*PD; Kidney|*DE/ME; Mycotoxins|*TO; Ochratoxins|ME/*TO
MeSH Heading: Animal; Food Microbiology; Human; Protein Binding; Rats

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0378-4274
Country of Publication: NETHERLANDS

Record 30 from database: MEDLINE
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Title: The kinase-dependent function of Lck in T-cell activation requires an intact site for tyrosine autophosphorylation.
Author: Xu H; Littman DR
Address: Department of Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco 94143-0414, USA.
Source: Ann N Y Acad Sci, 1995 Sep, 766:, 99-116
Abstract: The cytoplasmic protein tyrosine kinase p56lck (Lck) has important signaling roles in T-cell development and activation. We have mutated the two known regulatory tyrosine residues of CD4-associated Lck and examined the effects on its kinase-dependent function in an antigen-specific CD4-dependent T-cell hybridoma. Substitution of phenylalanine for the negative regulatory tyrosine-505 within a CD4/Lck chimera resulted in a slightly increased response to antigen, whereas mutation of the major in vitro autophosphorylation site (tyrosine-394) completely abolished the kinase-dependent function of Lck. Even though its kinase activity was only slightly affected, the F394 mutant behaved similarly to a catalytically inactive chimeric protein. Cross-linking of the F505 mutant, but not of wild-type Lck or F394 mutants, resulted in tyrosine phosphorylation of multiple cellular proteins. Although the pattern of tyrosine phosphorylation resembled that observed upon T-cell receptor cross-linking, there was no induction of interleukin-2 synthesis upon cross-linking of the chimeric protein. These results suggest that the activity of the Lck kinase domain in vivo is controlled by dephosphorylation at the negative regulatory site and phosphorylation at the positive regulatory (autophosphorylation) site. Additionally, our data show that the specific kinase activity of Lck towards an artificial substrate need not correlate with its ability to phosphorylate cellular proteins or its biological function.
Language of Publication: English
Unique Identifier: 96049629

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MeSH Heading (Major): src-Family Kinases|BI/*ME; Lymphocyte Transformation|*; T-Lymphocytes|EN/*IM
MeSH Heading: Animal; Antigens, CD4|BI/ME; Cells, Cultured; Chimeric Proteins|BI/ME; Human; Kinetics; Mutagenesis, Site-Directed; Phosphorylation; Phosphotyrosine|AN; Substrate Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Transfection; Tyrosine

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0077-8923
Country of Publication: UNITED STATES

Record 31 from database: MEDLINE
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Title: Diagnosis and management of tyrosinemia type I.
Author: Holme E; Lindstedt S
Address: GÂoteborg University, Gothenburg, Sweden.
Source: Curr Opin Pediatr, 1995 Dec, 7:6, 726-32
Abstract: Hereditary tyrosinemia type I (HTI) (MIM 276700) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (EC 3.7.1.2), which is the last enzyme in the tyrosine degradation pathway. The enzyme block causes accumulation of toxic metabolites in the liver and kidneys, which are the organs where tyrosine is mainly degraded. The disorder is characterized by severe liver disease, which either causes liver failure in infancy or may take a more protracted course, with death often occurring during childhood or adolescence because of hepatoma development. Treatment with a diet restricted in phenylalanine nd tyrosine does not prevent progression of the liver disease and development of hepatocellular carcinoma. Liver transplantation was previously the only option for these patients. Important achievements from metabolic and molecular biology studies of the disease include a new treatment for patients with HTI using an enzyme inhibitor, detection of self-induced correction of the genetic defect in regenerative liver nodules in HTI patients, identification and development of useful animal models for HTI, and studies of the molecular genetics of HTI. These advances will have great implications for our understanding of pathogenetic mechanisms, which is the basis for improved diagnostic methods and improved treatment of patients with HTI.
Language of Publication: English
Unique Identifier: 96372203

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|*DI/*TH; Tyrosine|*BL
MeSH Heading: Animal; Cyclohexanones|TU; Disease Models, Animal; Enzyme Inhibitors|TU; Gene Therapy; Human; Liver Transplantation; Nitrobenzoates|TU; Phenotype; Support, Non-U.S. Gov't; 4-Hydroxyphenylpyruvate Dioxygenase|AI

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1040-8703
Country of Publication: UNITED STATES

Record 32 from database: MEDLINE
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Title: Phenylketonuria: contemporary screening and diagnosis.
Author: Mabry CC
Address: Department of Pediatrics, University of Kentucky, Lexington 40536.
Source: Ann Clin Lab Sci, 1990 Nov-Dec, 20:6, 393-7
Abstract: Screening newborns for phenylketonuria (PKU) is a mandatory practice based on measuring a raised blood phenylalanine level. Many factors influence the rate of blood phenylalanine rise so that there are many pitfalls in detecting the 1:10,000 affected infant. About one percent of all babies tested proves to be "false positives." Two-thirds of those with persistent hyperphenylalaninemia prove to have classic PKU. Non-classic PKU with less intense, persistent hyperphenylalaninemia is due to different alterations in the enzyme, phenylalanine hydroxylase. Additionally, about one percent of the confirmed positive patients is due to either a defect in the synthesis or regeneration of the cofactor, tetrahydrobiopterin; these latter forms are not amenable to treatment with the low phenylalanine diet. Screening programs have developed directives regarding the timing and conditions for obtaining the specimens for testing. Specific confirmatory tests of those with positive results must be performed. Even so, about one in 70 affected babies is "missed," resulting in mental retardation, seizures, and neurologic deficits.
Language of Publication: English
Unique Identifier: 91158265

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MeSH Heading (Major): Neonatal Screening|*/MT; Phenylketonuria|DI/*PC
MeSH Heading: False Positive Reactions; Human; Infant, Newborn; Phenylalanine|BL

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0091-7370
Country of Publication: UNITED STATES
CAS Registry/EC Number: 3617-44-5 (Phenylalanine)

Record 33 from database: MEDLINE
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Title: Functions of the cystic fibrosis transmembrane conductance regulator protein.
Author: Frizzell RA
Address: Department of Physiology and Biophysics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham 35294-0005.
Source: Am J Respir Crit Care Med, 1995 Mar, 151:3 Pt 2, S54-8
Abstract: Cloning of the cystic fibrosis (CF) gene through genetic linkage analysis has led to new discoveries concerning the function of ion channels and disease mechanisms. Current understanding of CF indicates that epithelial cells from CF patients have reduced Cl- permeability, which impairs fluid and electrolyte secretion and results in luminal dehydration. There is also evidence that the cystic fibrosis transmembrane conductance regulator (CFTR) is the cyclic AMP-dependent ion channel whose activation is defective in CF cells. The CFTR is composed of 1480 amino acids that reveal a structural homology to a family of transport proteins termed the transport ATPases. The nucleotide-binding domains of CFTR are the locus of many disease-causing mutations; the common mutation in CFTR is deletion of a phenylalanine at position 508. In addition, CFTR contains a regulatory domain with consensus sites for phosphorylation by protein kinases. Reversible phosphorylation is a regulatory feature of the signal transduction pathway in which the CF defect lies. The phosphorylated channel requires the continuous presence of ATP, whether in the form of ATP binding or hydrolysis, to maintain channel activity. Channel activation requiring ATP can be inhibited by simultaneous presence of ADP, showing that this nucleotide diphosphate competes with ATP for activation. Studies of mutant CFTR expression indicate that at least two basic mechanisms are responsible for the CF phenotype, including CFTR protein dysfunction and inappropriate protein targeting. If mechanisms for bringing this partially functional protein to the plasma membrane can be found, the airway disease of the vast majority of patients with CF could be improved.
Language of Publication: English
Unique Identifier: 95187463

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MeSH Heading (Major): Chloride Channels|GE/*PH/SE; Cystic Fibrosis|GE/*ME; Membrane Proteins|GE/*PH
MeSH Heading: Cyclic AMP|PH; Human; Ion Channel Gating|PH; Phosphorylation; Sequence Deletion; Sequence Homology, Amino Acid; Signal Transduction|GE; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1073-449X
Country of Publication: UNITED STATES

Record 34 from database: MEDLINE
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Title: Postinjury neutrophil priming and activation states: therapeutic challenges [editorial]
Author: Botha AJ; Moore FA; Moore EE; Fontes B; Banerjee A; Peterson VM
Address
Source: Shock, 1995 Mar, 3:3, 157-66
Abstract: Both hyperactivity and hypoactivity of neutrophils (PMNs) have been implicated in the pathogenesis of postinjury multiple organ failure. In this paper, the cellular and molecular mechanisms involved in the regulation of PMN O2- production are reviewed. In addition, relevant research laboratory techniques for measuring both intracellular and extracellular O2- release are outlined. In a pilot study PMN O2- release in response to a battery of PMN agonists was determined, and four functional states of the NADPH were defined: resting, primed, activated, and unresponsive. PMNs from normal adult volunteers are in the resting state. In contrast, PMNs from patients with severe torso trauma are primed and activated in the first 24 h postinjury, but, after 48 h, become unresponsive to both receptor-dependent (platelet activating factor and N-formyl-methyl-leucyl-phenylalanine) and receptor-independent (phorbol 12-myristate 13-acetate) activation. The ability to identify at-risk patients and provide a rationale for ameliorating PMN-mediated tissue injury in patients with hyperinflammation syndromes are discussed. In addition, the importance of identifying patients with PMNs that are unresponsive, and the necessity for increasing PMN function in these patients in order to reduce the risk of sepsis, are also discussed.
Language of Publication: English
Unique Identifier: 95292111

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MeSH Heading (Major): Multiple Organ Failure|EN/*ME/*TH; Neutrophils|EN/*PH; Wounds and Injuries|EN/*ME/*TH
MeSH Heading: Human; NADH, NADPH Oxidoreductases

Publication Type: EDITORIAL; REVIEW; REVIEW, TUTORIAL
ISSN: 1073-2322
Country of Publication: UNITED STATES

Record 35 from database: MEDLINE
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Title: Phenylethylamine modulation of affect: therapeutic and diagnostic implications.
Author: Sabelli HC; Javaid JI
Address: Department of Psychiatry, Rush Medical Center, Chicago, IL 60612, USA.
Source: J Neuropsychiatry Clin Neurosci, 1995 Win, 7:1, 6-14
Abstract: A review of the literature indicates that brain phenylethylamine (PEA) may be a neuromodulator of aminergic synapses and that it promotes energy, elevates mood, and favors aggression. Phenylacetic acid, the main metabolite of PEA, is decreased in the biological fluids of depressed subjects and schizophrenic subjects and is increased in schizoaffective subjects. The administration of PEA or of its precursor L-phenylalanine improves mood in depressed patients treated with a selective monoamine oxidase B inhibitor. The authors speculate that studies of PEA metabolism may have diagnostic value and that PEA administration may be therapeutic in selected depressed patients.
Language of Publication: English
Unique Identifier: 95226903

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MeSH Heading (Major): Affect|*DE; Mental Disorders|DT/*ME; Phenethylamines|*ME/*PD/TU; Psychotropic Drugs|*PD/TU
MeSH Heading: Brain|DE; Human; Support, Non-U.S. Gov't; Synapses|DE

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0895-0172
Country of Publication: UNITED STATES

Record 36 from database: MEDLINE
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Title: Painful keratoderma and photophobia: hallmarks of tyrosinemia type II.
Author: Rabinowitz LG; Williams LR; Anderson CE; Mazur A; Kaplan P
Address: Department of Pediatrics, Medical College of Wisconsin, Milwaukee.
Source: J Pediatr, 1995 Feb, 126:2, 266-9
Abstract: Tyrosinemia type II (Richner-Hanhart syndrome), which is caused by a deficiency of hepatic tyrosine aminotransferase, results in elevated plasma and urinary tyrosine concentrations. We describe a young boy who was seen at 6 months of age with red eyes, photophobia, and eye pain that were not suspected to be caused by tyrosinemia II until painful plantar keratoderma developed at 2 1/2 years of age. Treatment with a diet low in tyrosine and phenylalanine reversed the manifestations of the disease.
Language of Publication: English
Unique Identifier: 95147122

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|CO/DH/*DI; Keratoderma, Palmoplantar|DH/*DI/ET; Light|*AE; Tyrosine|*BL
MeSH Heading: Case Report; Child, Preschool; Human; Male

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW OF REPORTED CASES
ISSN: 0022-3476
Country of Publication: UNITED STATES

Record 37 from database: MEDLINE
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Title: Regulation of the activity of hepatic phenylalanine hydroxylase.
Author: Kaufman S
Address
Source: Adv Enzyme Regul, 1986, 25:, 37-64
Abstract: Rat liver phenylalanine hydroxylase catalyzes the tetrahydropterin-dependent oxidation of phenylalanine to tyrosine, according to equation 1. In addition to the naturally-occurring coenzyme, tetrahydrobiopterin (BH4), certain synthetic analogs of BH4 such as 6-methyltetrahydropterin (6MPH4) have high cofactor activity. (formula; see text) The hydroxylase can be activated by a variety of reversible and irreversible modifications, including those caused by partial proteolysis, by interaction with phospholipids such as lysolecithin, by alkylation of a single sulfhydryl group, by phosphorylation catalyzed by cAMP-dependent protein kinase, and by preincubation with its substrate, phenylalanine. All of these modes of activation greatly increase the hydroxylase activity in the presence of BH4, whereas the activity in the presence of 6MPH4 is increased only slightly. The ratio of hydroxylase activity in the presence of BH4 compared to the activity in the presence of 6MPH4, therefore, is a useful index of the state of activation of the enzyme. Of the various activation mechanisms listed above, only phosphorylation of the enzyme and phenylalanine-activation appear to operate in vivo. The evidence indicates that these two regulatory mechanisms act synergistically. Thus, phosphorylation of the enzyme by cAMP-dependent protein kinase is stimulated by phenylalanine, especially in the presence of BH4, (which by itself inhibits), whereas phosphorylation sensitizes the enzyme to activation by phenylalanine. One of the consequences of these interlocking control mechanisms is to enhance the responsiveness of the activity of the hydroxylase to alterations in tissue levels of phenylalanine. As a result, elevated concentrations of phenylalanine can be rapidly metabolized, thereby protecting the fetal and neonatal brain from possible damage by excess phenylalanine.
Language of Publication: English
Unique Identifier: 87123881

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MeSH Heading (Major): Liver|DE/*EN; Phenylalanine Hydroxylase|*ME
MeSH Heading: Animal; Biopterin|AA/ME; Diet; Enzyme Activation; Glucagon|PD; Human; Ligands; Phenylalanine|ME; Phosphoprotein Phosphatase|ME; Phosphorylation; Rats

Publication Type: JOURNAL ARTICLE; REVIEW
ISSN: 0065-2571
Country of Publication: ENGLAND
CAS Registry/EC Number: EC 1.14.16.1 (Phenylalanine Hydroxylase); EC 3.1.3.- (phenylalanine hydroxylase phosphatase); EC 3.1.3.16 (Phosphoprotein Phosphatase); 0 (Ligands); 17528-72-2 (5,6,7,8-tetrahydrobiopterin); 22150-76-1 (Biopterin); 3617-44-5 (Phenylalanine); 9007-92-5 (Glucagon)

Record 38 from database: MEDLINE
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Title: Formation, nutritional value, and safety of D-amino acids.
Author: Friedman M
Address: Western Regional Research Center, U.S. Department of Agriculture, Albany, California 94710.
Source: Adv Exp Med Biol, 1991, 289:, 447-81
Abstract: The extent of racemization of L-amino acid residues to D-isomers in food proteins increases with pH, time, and temperature. The nutritional utilization of different D-amino acids vary widely, both in animals and humans. In addition, some D-amino acids may be deleterious. For example, although D-phenylalanine is nutritionally available as a source of L-phenylalanine, high concentrations of D-tyrosine inhibit the growth of mice. The antimetabolic effect of D-tyrosine can be minimized by increasing the L-phenylalanine content of the diet. Similarly, L-cysteine has a sparing effect on L-methionine when fed to mice; however, D-cysteine does not. The wide variation in the utilization of D-amino acids is exemplified by the fact that D-lysine is not utilized as a source of L-lysine, whereas the utilization of D-methionine as a source of the L-isomer for growth is dose-dependent, reaching 76% of the value obtained with L-methionine. Both D-serine and the mixture of L-L and L-D isomers of lysinoalanine induce histological changes in the rat kidneys. D-tyrosine, D-serine, and lysinoalanine are produced in significant amounts under the influence of even short periods of alkaline treatment. Unresolved is whether the biological effects of D-amino acids vary, depending on whether they are consumed in the free state or as part of a food protein. Possible, metabolic interaction, antagonism, or synergism among D-amino acids in vivo also merits further study. The described results with mice complement related studies with other species and contribute to the understanding of nutritional and toxicological consequences of ingesting D-amino acids. Such an understanding will make it possible to devise food processing conditions to minimize or prevent the formation of undesirable D-amino acids in food proteins and to prepare better and safer foods.
Language of Publication: English
Unique Identifier: 91377540

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MeSH Heading (Major): Amino Acids|AE/CH/*ST; Dietary Proteins|AE/*CH/ME/ST
MeSH Heading: Animal; Dose-Response Relationship, Drug; Human; Nutritive Value; Stereoisomerism; Weight Gain

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0065-2598
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amino Acids); 0 (Dietary Proteins)

Record 39 from database: MEDLINE
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Title: In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function.
Author: Waters PJ; Parniak MA; Nowacki P; Scriver CR
Address: Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Source: Hum Mutat, 1998, 11:1, 4-17
Abstract: Mutations in the human phenylalanine hydroxylase gene (PAH) altering the expressed cDNA nucleotide sequence (GenBank U49897) can impair activity of the corresponding enzyme product (hepatic phenylalanine hydroxylase, PAH) and cause hyperphenylalaninemia (HPA), a metabolic phenotype for which the major disease form is phenylketonuria (PKU; OMIM 261600). In vitro expression analysis of inherited human mutations in eukaryotic, prokaryotic, and cell-free systems is informative about the mechanisms of mutation effects on enzymatic activity and their predicted effect on the metabolic phenotype. Corresponding analysis of site-directed mutations in rat Pah cDNA has assigned critical functional roles to individual amino acid residues within the best understood species of phenylalanine hydroxylase. Data on in vitro expression of 35 inherited human mutations and 22 created rat mutations are reviewed here. The core data are accessible at the PAH Mutation Analysis Consortium Web site (http://www.mcgill.ca/pahdb).
Language of Publication: English
Unique Identifier: 98111373

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MeSH Heading (Major): Gene Expression Regulation, Enzymologic|*; Mutation|*; Phenylalanine Hydroxylase|*CH/*GE/PH
MeSH Heading: Animal; DNA Mutational Analysis; Genotype; Human; Phenotype; Structure-Activity Relationship; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1059-7794
Country of Publication: UNITED STATES

Record 40 from database: MEDLINE
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Title: Hydroxylation of salicylate and phenylalanine as assays for hydroxyl radicals: a cautionary note visited for the third time.
Author: Halliwell B; Kaur H
Address: Neurodegenerative Disease Research Centre, King's College, London, UK.
Source: Free Radic Res, 1997 Sep, 27:3, 239-44
Abstract: Hydroxylation of salicylate to 2,3- and 2,5-dihydroxy-benzoates (DHBs) is widely used as an index of hydroxyl radical (OH.) formation in vivo and in vitro. Several recent studies indicate that peroxynitrite can lead to generation of DHBs from salicylate and it is uncertain as to whether or not OH. is involved. A similar problem may occur in the use of phenylalanine as an OH. detector. Hence formation of hydroxylation products from salicylate (or phenylalanine) may not in itself be a definitive index of OH. generation, especially in cases where such generation in physiological systems is decreased by inhibitors of nitric oxide synthase. Determination of salicylate (or phenylalanine) nitration products can allow distinction between peroxynitrite-dependent aromatic hydroxylation and that involving "real" OH..
Language of Publication: English
Unique Identifier: 98011512

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MeSH Heading (Major): Hydroxyl Radical|*AN/ME; Phenylalanine|AA/*CH/ME; Salicylic Acids|*CH/ME
MeSH Heading: Animal; Chromatography, High Pressure Liquid|MT; Human; Hydroxylation; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1071-5762
Country of Publication: SWITZERLAND

Record 41 from database: MEDLINE
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Title: The effects of high phenylalanine concentration on chick embryonic development.
Author: Kirby ML; Miyagawa ST
Address: Department of Anatomy, Medical College of Georgia, Augusta 30912-2000.
Source: J Inherit Metab Dis, 1990, 13:4, 634-40
Abstract: Cells from a particular portion of the cranial neural crest (cardiac neural crest) migrate from the neural fold into pharyngeal arches 3, 4 and 6, where they provide the support for the endothelium of the aortic arch arteries, and by migration into the outflow tract become involved in septation of the truncus arteriosus. Ablation of the premigratory cardiac neural crest results in persistent truncus arteriosus and other defects reminiscent of the DiGeorge syndrome in man. Removal of a small area of the cardiac neural crest causes a spectrum of heart defects classified together as dextraposed aorta including changes like that of Fallot's tetralogy in man. Some inflow tract anomalies have also been found. Pilot studies injecting phenylalanine into developing chick embryos at a very early stage had little effect on embryo viability or on the incidence of congenital heart defects. However, sham-treated animals produced predominantly small simple ventricular septal defects but phenylalanine-treated embryos had more serious and complex heart anomalies. It is not possible to say yet that congenital heart disease in the offspring of mothers with untreated phenylketonuria is due to phenylalanine-induced damage to the neural crest, but the pilot studies in chick suggest that this idea is worth pursuing.
Language of Publication: English
Unique Identifier: 91040687

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MeSH Heading (Major): Heart Defects, Congenital|CO/*DT/PA; Neural Crest|DE/*ME/PA; Phenylalanine|*PD; Phenylketonuria|CO/*DT/PA
MeSH Heading: Animal; Chick Embryo; Human; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0141-8955
Country of Publication: NETHERLANDS
CAS Registry/EC Number: 3617-44-5 (Phenylalanine)

Record 42 from database: MEDLINE
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Title: Pteridines and mono-amines: relevance to neurological damage.
Author: Smith I; Howells DW; Hyland K
Address
Source: Postgrad Med J, 1986 Feb, 62:724, 113-23
Abstract: Patients with phenylalanine hydroxylase deficiency show increased concentrations of biopterins and neopterins, and reduced concentrations of serotonin and catecholamines, when phenylalanine concentrations are raised. The pterin rise reflects increased synthesis of dihydroneopterin and tetrahydrobiopterin, and the amine fall a reduction in amine synthesis due to inhibition by phenylalanine of tyrosine and tryptophan transport into neurones. The pterin and amine changes appear to be independent of each other and are present in the central nervous system as well as the periphery; they disappear when phenylalanine concentrations are reduced to normal. Patients with arginase deficiency show a similar amine disturbance but have normal pterin levels. The amine changes probably contribute neurological symptoms but pterin disturbance is not known to affect brain function. Patients with defective biopterin metabolism exhibit severely impaired amine synthesis due to tetrahydrobiopterin deficiency. Pterin concentrations vary with the site of the defect. Symptoms include profound hypokinesis and other features of basal ganglia disease. Neither symptoms nor amine changes are relieved by controlling phenylalanine concentrations. Patients with dihydropteridine reductase (DHPR) deficiency accumulate dihydrobiopterins and develop secondary folate deficiency which resembles that occurring in patients with defective 5,10-methylene tetrahydrofolate reductase activity. The latter disorder is also associated with Parkinsonism and defective amine and pterin turnover in the central nervous system, and a demyelinating illness occurs in both disorders. In DHPR deficiency cerebral calcification may develop in a similar distribution to that seen in congenital folate malabsorption and methotrexate toxicity. Symptoms are ameliorated by therapy with 5-formyltetrahydrofolate but exacerbated by folic acid.
Language of Publication: English
Unique Identifier: 87092139

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MeSH Heading (Major): Amines|*ME; Nervous System|*ME; Phenylketonuria|*ME; Pteridines|*ME
MeSH Heading: Biopterin|AA/DF/ME; Folic Acid|ME; Human; Phenylalanine|BL; Phenylalanine Hydroxylase|DF; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW
ISSN: 0032-5473
Country of Publication: ENGLAND
CAS Registry/EC Number: EC 1.14.16.1 (Phenylalanine Hydroxylase); 0 (Amines); 0 (Pteridines); 17528-72-2 (5,6,7,8-tetrahydrobiopterin); 22150-76-1 (Biopterin); 3617-44-5 (Phenylalanine); 59-30-3 (Folic Acid)

Record 43 from database: MEDLINE
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Title: White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings.
Author: Bick U; Ullrich K; Stöber U; Möller H; Schuierer G; Ludolph AC; Oberwittler C; Weglage J; Wendel U
Address: Department of Radiology, University of Münster, Germany.
Source: Eur J Pediatr, 1993 Dec, 152:12, 1012-20
Abstract: In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n = 8) and/or 1H spectroscopy (n = 7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6- to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T2 relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T2 relaxometry showed a bi-exponential behaviour of T2 in the affected white matter, with a slow component of about 200-450 ms, indicating an increase in free (extracellular) water. 1H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.
Language of Publication: English
Unique Identifier: 94178318

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|*CO/PA; Brain|*PA; Brain Diseases|*ET/PA; Phenylalanine|*BL; Phenylketonuria|*CO/PA
MeSH Heading: Adolescence; Adult; Female; Human; Magnetic Resonance Imaging; Male; Nuclear Magnetic Resonance

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW OF REPORTED CASES
ISSN: 0340-6199
Country of Publication: GERMANY
CAS Registry/EC Number: 3617-44-5 (Phenylalanine)

Record 44 from database: MEDLINE
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Title: Tetrahydrobiopterin deficiencies: preliminary analysis from an international survey.
Author: Dhondt JL
Address
Source: J Pediatr, 1984 Apr, 104:4, 501-8
Abstract: Tetrahydrobiopterin deficiency is a rare cause of hyperphenylalaninemic syndromes. The natural history of the disease is characterized by progressive neurologic illness unresponsive to a phenylalanine-restricted diet. Fifty patients have been reported. From the documented cases, the following statements can be made: (1) An incidence of 2% among hyperphenylalaninemic babies can be reasonably estimated. (2) Most patients have high neonatal blood phenylalanine concentrations, but some have only mild elevations. (3) Among the available diagnostic tests, measurement of urine pteridines should be proposed in all hyperphenylalaninemic babies, (4) The tolerance to dietary phenylalanine is generally high. (5) The results of neurotransmitter replacement therapy are encouraging, but treatment should be started within the first month and requires a strict follow-up protocol. Consequently, in every newborn infant with positive Guthrie test results, a rapid investigation of BH4 metabolism should be accomplished in order to differentiate between phenylalanine-hydroxylase deficiencies (phenylketonuria, mild hyperphenylalaninemia, transient hyperphenylalaninemia) and BH4 deficiencies.
Language of Publication: English
Unique Identifier: 84164247

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|DH/*DI/DT/GE; Biopterin|AA/*DF/TU; Pteridines|*DF
MeSH Heading: Adjuvants, Pharmaceutic; Alcohol Oxidoreductases|DF; Dihydropteridine Reductase|DF; Female; Folic Acid|ME; GTP Cyclohydrolase|DF; Human; Infant; Infant, Newborn; Male; Neurotransmitters|ME; Phenylalanine|ME; Phenylketonuria|ME

Publication Type: JOURNAL ARTICLE; REVIEW
ISSN: 0022-3476
Country of Publication: UNITED STATES
CAS Registry/EC Number: EC 1.1 (Alcohol Oxidoreductases); EC 1.1.- (7,8-dihydrobiopterin synthetase); EC 1.6.99.7 (Dihydropteridine Reductase); EC 3.5.4.16 (GTP Cyclohydrolase); 0 (Adjuvants, Pharmaceutic); 0 (Neurotransmitters); 0 (Pteridines); 17528-72-2 (5,6,7,8-tetrahydrobiopterin); 22150-76-1 (Biopterin); 3617-44-5 (Phenylalanine); 59-30-3 (Folic Acid)

Record 45 from database: MEDLINE
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Title: Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia.
Author: Degrell I; Hellsing K; Nagy E; Niklasson F
Address: Department of Neurology and Psychiatry, University Medical School of Debrecen, Hungary.
Source: Arch Gerontol Geriatr, 1989 Sep-Oct, 9:2, 123-35
Abstract: Free amino acid levels were measured in cerebrospinal fluid (CSF) from demented patients (D, n = 30) suffering from presenile and senile dementia of Alzheimer type (PDAT, n = 7; SDAT, n = 9), multi-infarct dementia (MID, n = 14) and a reference sample group consisting of young neurotic patients (R, n = 16). Comparing the amino acid levels in the dementia subgroups, significantly higher alanine, methionine, phenylalanine and tyrosine levels were found both in MID and SDAT vs. PDAT. No difference was seen between SDAT and MID. Compared to the reference sample group, higher glycine levels were found in each dementia subgroup; higher alanine, methionine and ornithine levels in MID, and SDAT; and higher phenylalanine levels in MID. In PDAT the level of tyrosine was lower. Coefficients of correlation were calculated between amino acid levels and age, and the findings in the reference sample groups were divergent from those observed in dementia. The differences observed are discussed in terms of amino acid, carbohydrate and neurotransmitter metabolism.
Language of Publication: English
Unique Identifier: 90073115

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MeSH Heading (Major): Alzheimer's Disease|*CF; Amino Acids|*CF; Dementia, Multi-Infarct|*CF
MeSH Heading: Age Factors; Aged; Aged, 80 and over; Female; Human; Male; Middle Age; Sex Factors; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW LITERATURE
ISSN: 0167-4943
Country of Publication: NETHERLANDS
CAS Registry/EC Number: 0 (Amino Acids)

Record 46 from database: MEDLINE
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Title: Nutritional therapy for selected inborn errors of metabolism.
Author: Levy HL
Address: Harvard Medical School, Boston, Massachusetts.
Source: J Am Coll Nutr, 1989, 8 Suppl:, 54S-60S
Abstract: Nutritional approaches are available for the management of several different classes of inborn metabolism errors. In phenylketonuria (PKU), phenylalanine is not properly metabolized; and its accumulation leads to neurologic dysfunction and metal retardation. Altering the diet to limit phenylalanine intake led to remarkable improvement in children with PKU. It was later found that instituting dietary therapy immediately after identification of the disorder in newborns prevented mental retardation. Throughout the 1960s nutritional therapies were found for other inborn disorders, including galactosemia, maple syrup urine disease, and homocystinuria. For the group of disorders associated with defects in the urea cycle, leading to profound hyperammonemia, therapy based on the concept of waste nitrogen excretion (i.e., by increasing excretion of urea cycle intermediates in the urine, nitrogen that would otherwise recycle as ammonia can be eliminated) dramatically produced better control of hyperammonemia and its consequences. Some inborn errors of metabolism respond to vitamin therapy. Biotin-related multiple carboxylase synthetase deficiency can be produced by either of two enzyme defects--holocarboxylase synthetase deficiency or biotinidase deficiency. Both are treatable with biotin supplementation. The symptoms of multiple carboxylase deficiency can also occur after intestinal resection or ingestion of raw eggs. Multiple carboxylase deficiency has been treated successfully in utero by giving the mother biotin supplements. Peroxisomal disorders may respond to dietary management. Liver disease in hereditary tyrosinemia may be accentuated by hypermethioninemia and treated by controlling the blood methionine level. Glycogen storage disease Type I, which causes hypoglycemia, can be controlled by oral administration of cornstarch.
Language of Publication: English
Unique Identifier: 90038080

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MeSH Heading (Major): Metabolism, Inborn Errors|*DH; Nutrition|*
MeSH Heading: Glycogen Storage Disease Type I|DH; Human; Microbodies; Multiple Carboxylase Deficiency|DH; Research; Support, U.S. Gov't, P.H.S.; Tyrosine|BL; Urea|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0731-5724
Country of Publication: UNITED STATES
CAS Registry/EC Number: 55520-40-6 (Tyrosine); 57-13-6 (Urea)

Record 47 from database: MEDLINE
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Title: Amino acid metabolism in uremia.
Author: Fürst P
Address: Institute for Biological Chemistry and Nutrition, University of Hohenheim, Stuttgart, Federal Republic of Germany.
Source: J Am Coll Nutr, 1989 Aug, 8:4, 310-23
Abstract: The uremic syndrome is multifactorial, and affects most tissues and organs. Disturbances in protein and amino acid metabolism may play important roles, especially in chronic uremia, either directly or by production of toxic metabolites, with resultant negative nitrogen (N) balance, muscle wasting, reduced protein synthesis, and characteristically abnormal intracellular free amino acid concentrations. There are also grossly abnormal amino acid levels in the plasma of uremic patients, e.g., increases in conjugated amino acids, high levels of several nonessential and low levels of essential amino acids. The ratios of tyrosine/phenylalanine and of valine/glycine are decreased. The low tryptophan levels may contribute to encephalopathy as a result of an imbalance in neurotransmitter synthesis. Citrulline is found in excess; the explanation is unresolved. There are elevated concentrations of the sulfur-containing amino acids: cystine, taurine, cystathionine, and homocysteine. Excess of the latter is implicated in the atherogenesis of renal failure. Disturbed metabolism and interorgan exchange of amino acids in the uremic state explains some of the abnormalities in tissue and plasma concentrations of individual amino acids. Enzymatic defects are involved in the disturbed metabolism of branched chain amino acids (BCAA), with possible antagonism among them, which impairs growth and amino acid utilization. Carbohydrate intolerance, associated with insensitivity of peripheral tissues to insulin and hyperinsulinemia, elicits decreased plasma BCAA. Protein synthesis rates in normal and pathological conditions are more closely related to the intracellular amino acid pool than to plasma amino acid levels. Concentrations of individual amino acids in the plasma pool are poor indicators of their intracellular concentrations. Muscle contains the largest pool of protein and free amino acids in the body. In chronic renal failure patients, the intracellular concentrations of valine, threonine, lysine, and carnosine are low. With low protein diets and in hemodialysis, serine, tyrosine, and taurine often are also low. The low taurine may be related to fatigue and to uremic cardiomyopathies. The commonly used amino acid supplements generally fail to correct the intracellular amino acid deficits. A "New Formula" has been developed to correct these intracellular amino acid abnormalities, and to supplement a low protein diet. It provides more valine than leucine, increased tyrosine and threonine, and less histidine, leucine, isoleucine, lysine, methionine, and phenylalanine than in formulas customarily used for patients with chronic renal failure. It is uncertain whether other ap
Language of Publication: English
Unique Identifier: 89381140

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MeSH Heading (Major): Amino Acids|*ME; Uremia|*ME
MeSH Heading: Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW LITERATURE
ISSN: 0731-5724
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amino Acids)

Record 48 from database: MEDLINE
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Title: Use of cetirizine to investigate non-H1 effects of second-generation antihistamines.
Author: Townley RG; Okada C
Address: Department of Medicine, Creighton University School of Medicine, Omaha, Nebraska.
Source: Ann Allergy, 1992 Feb, 68:2, 190-6
Abstract: In addition to their increased potency as H1 blockers and their nonsedating effects, the second-generation antihistamines have other unusual and potentially beneficial properties. Evidence is accumulating from several laboratories that at least one of these agents under investigation, cetirizine, may be effective in inhibiting the late reaction. The Johns Hopkins group showed that during the cutaneous late phase response (LPR), histamine release was not altered by cetirizine, 20 mg, pretreatment. The most dramatic effect of cetirizine was attenuation of inflammatory cell migration into the chamber. Eosinophils, neutrophils, and basophils were reduced by about 75% during hours 6 to 8. It can be concluded that cetirizine influences the LPR by causing a reduction in the inflammatory cell infiltrate. Cetirizine, 10 mg, orally once a day also induced a significant decrease in the wheal and flare skin reactions caused by pollen, histamine, and compound 48/80. Cetirizine inhibited eosinophil recruitment and platelet-activating factor (PAF) in skin chambers 24 hours after pollen challenge. We and others have studied the mechanisms of this effect. The release of eosinophil peroxidase induced by PAF and formyl-methionyleucyl/phenylalanine was not attenuated by cetirizine. At therapeutic concentrations, however, cetirizine has a potent inhibitory action in vitro on eosinophil chemotaxis induced either by formyl-methionyleucyl/phenylalanine or PAF and also on IgE-dependent stimulation of platelets. In a separate study in patients with chronic urticaria, cetirizine markedly reduced both the immediate wheal and flare induced by PAF and the delayed reaction at six hours. These results suggest that cetirizine acts on eosinophil migration to inhibit the late reaction.
Language of Publication: English
Unique Identifier: 92152455

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MeSH Heading (Major): Histamine Antagonists|*PD; Histamine H1 Antagonists|*PD; Hydroxyzine|*AA/PD
MeSH Heading: Human; Hypersensitivity|DT; Hypersensitivity, Delayed|PC; Nose|IM; Skin|IM; Urticaria|DT

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0003-4738
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Histamine Antagonists); 0 (Histamine H1 Antagonists); 68-88-2 (Hydroxyzine); 83881-51-0 (Cetirizine)

Record 49 from database: MEDLINE
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Title: Nurses' role in preventing birth defects in offspring of women with phenylketonuria [published erratum appears in J Obstet Gynecol Neonatal Nurs 1992 Sep-Oct;21(5):352]
Author: Acosta PB; Wright L
Address: Ross Laboratories, Columbus, Ohio.
Source: J Obstet Gynecol Neonatal Nurs, 1992 Jul-Aug, 21:4, 270-6
Abstract: Most women who began nutrition support as neonates for a diagnosis of phenylketonuria, an inherited defect in phenylalanine metabolism, are of normal intelligence, no longer require a restricted diet, and wish to have children of their own. Phenylketonuria that is untreated when a woman conceives and during gestation results in poor reproductive outcomes. Treatment with and careful monitoring of a phenylalanine-restricted diet can improve reproductive outcome. Nurses have the primary responsibility in locating women of childbearing age with phenylketonuria; developing strategies to improve palatability of the diet, thereby enhancing compliance; providing ongoing monitoring and support of the mother-child dyad; and counseling couples at risk.
Language of Publication: English
Unique Identifier: 92356229

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MeSH Heading (Major): Abnormalities|ET/*PC; Phenylketonuria|CO/DT/*NU; Pregnancy Complications|DT/*NU; Pregnancy Outcome|*
MeSH Heading: Female; Human; Infant, Newborn; Mass Screening; Monitoring, Physiologic; Neonatal Screening; Preconception Care; Pregnancy; Prenatal Care

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0884-2175
Country of Publication: UNITED STATES

Record 50 from database: MEDLINE
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Title: Enzymology of the phenylalanine-hydroxylating system.
Author: Kaufman S
Address: Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, Md.
Source: Enzyme, 1987, 38:1-4, 286-95
Abstract: The phenylalanine-hydroxylating system consists of 3 essential components, phenylalanine hydroxylase (PAH), dihydropteridine reductase (DHPR) and the coenzyme, tetrahydrobiopterin (BH4). DHPR and BH4 are also essential components of the trosine- and tryptophan-hydroxylating systems. During the hydroxylation reaction, BH4 is converted to the quinonoid dihydrobiopterin. The reduction of this latter compound back to BH4 is catalyzed by the reductase in the presence of NADH. In addition to the classic form of phenylketonuria, which is caused by a lack of PAH, a form is caused by a lack of DHPR and another by a deficiency of BH4 caused by the lack of an enzyme involved in its de novo biosynthesis. Besides hyperphenylalaninemia, these variant forms are characterized by neurological deterioration.
Language of Publication: English
Unique Identifier: 88151858

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|*EN/TH; Biopterin|*AA/DF; Hydroxylases|*; Phenylalanine|*ME; Phenylalanine Hydroxylase|*DF/ME
MeSH Heading: Human; Hydroxylation

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0013-9432
Country of Publication: SWITZERLAND
CAS Registry/EC Number: EC 1.14. (Hydroxylases); EC 1.14.16.1 (Phenylalanine Hydroxylase); 17528-72-2 (5,6,7,8-tetrahydrobiopterin); 22150-76-1 (Biopterin); 3617-44-5 (Phenylalanine)

Record 51 from database: MEDLINE
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Title: Enzymatic catalysis by Friedel-Crafts-type reactions.
Author: Rétey J
Address: Institut fÂur Organische Chemie, UniversitÂat Karlsruhe, Germany.
Source: Naturwissenschaften, 1996 Oct, 83:10, 439-47
Abstract: Although most enzymes work in aqueous medium, at their active sites they can adjust the polarity to meet the requirements of the reactions they catalyse. Thus, a Friedel-Crafts-type electrophilic substitution which is normally conducted in water-free media, can be used to activate the substrate for chemically difficult transformations. It is shown that histidine and phenylalanine ammonia lyases which contain the rare prosthetic group dehydroalanine, make use of a Friedel-Crafts-type reaction which was formerly thought to occur only in rather abiotic conditions. While histidine ammonia-lyase catalyses the first step of histidine degradation in most cells, phenylalanine ammonia-lyase is an important plant enzyme, producing cinnamic acid which is the precursor of lignins, coumarins and flavonoids responsible for the marvelous colours of many flowers.
Language of Publication: English
Unique Identifier: 97103544

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MeSH Heading (Major): Enzymes|*CH/*ME; Histidine Ammonia-Lyase|*CH/*ME; Phenylalanine Ammonia-Lyase|*CH/*ME
MeSH Heading: Amino Acid Sequence; Animal; Catalysis; Comparative Study; Conserved Sequence; Human; Molecular Sequence Data; Point Mutation; Sequence Homology, Amino Acid; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0028-1042
Country of Publication: GERMANY

Record 52 from database: MEDLINE
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Title: Transport of amino acids by the human placenta: predicted effects thereon of maternal hyperphenylalaninaemia.
Author: Kudo Y; Boyd CA
Address: Department of Human Anatomy, Oxford University, UK.
Source: J Inherit Metab Dis, 1990, 13:4, 617-26
Abstract: Brush border and basal plasma membrane vesicles prepared from normal term human placental syncytiotrophoblast have been used to study amino acid transport. Such studies are reviewed and novel results presented which confirm that saturation of placental transport by phenylalanine is unlikely to limit delivery of this amino acid to the fetus even with grossly raised maternal concentrations. Such raised maternal levels of phenylalanine are, however, likely to severely embarrass the delivery to the fetus across the placental brush border membrane of L-tyrosine and, to a lesser extent, of L-tryptophan. Reasons for thinking that this may be relevant to the fetal damage found in maternal PKU are discussed.
Language of Publication: English
Unique Identifier: 91040685

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MeSH Heading (Major): Maternal-Fetal Exchange|*; Phenylalanine|*ME; Phenylketonuria|*ME; Placenta|*ME
MeSH Heading: Female; Human; Microvilli|ME; Pregnancy; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0141-8955
Country of Publication: NETHERLANDS
CAS Registry/EC Number: 3617-44-5 (Phenylalanine)

Record 53 from database: MEDLINE
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Title: The influence of mutations of enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency.
Author: Güttler F; Guldberg P
Address: John F. Kennedy Institute, Glostrup, Denmark.
Source: Eur J Pediatr, 1996 Jul, 155 Suppl 1:, S6-10
Abstract: The phenylalanine hydroxylase (PAH) deficiency trait is heterogeneous with a continuum of metabolic phenotypes ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). More than 200 mutations in the PAH gene are associated with PAH deficiency. From theoretical considerations or in vitro expression studies each mutation has a particular influence on enzyme activity, which explains the variation in dietary tolerance for phenylalanine (Phe). This paper gives a summary of the effect of each type of mutation on PAH activity and illustrates how the combination of mutations (the genotype) is associated with the Phe tolerance (the metabolic phenotype). Mutations within a population generally include a few prevalent mutations and a high number of rare mutations. The particular distribution of mutations implies that many PAH-deficient patients carry the same mutation combination, enabling the establishment of genotype-phenotype correlations by comparing clinical parameters in patients with identical genotypes. Because certain mutations always cause MHP irrespective of the mutation on the second allele, mutation typing of hyperphenylalaninaemic neonates will differentiate between PKU and MHP. In addition, genotyping will provide a tool for precise diagnosis of the metabolic phenotype of the neonate with PKU and thereby permit earlier implementation of dietary therapy better tailored to each individual patient.
Language of Publication: English
Unique Identifier: 96426306

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|EN/*GE; Mutation|*GE; Phenylalanine Hydroxylase|*DF/GE/ME; Phenylketonuria|*GE
MeSH Heading: Codon|GE; Cognition Disorders|GE; Enzyme Activation|GE; Genotype; Homeostasis|GE; Human; Phenotype; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0340-6199
Country of Publication: GERMANY

Record 54 from database: MEDLINE
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Title: Gene therapy for phenylketonuria.
Author: Eisensmith RC; Woo SL
Address: Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Source: Eur J Pediatr, 1996 Jul, 155 Suppl 1:, S16-9
Abstract: Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). Limitations of the current dietary treatment for PKU have led to the development of potential treatments based on somatic gene transfer. Three different vector systems have been examined. Vectors derived from a recombinant retrovirus or a DNA/protein complex can efficiently transduce the PAH cDNA into PAH-deficient hepatocytes in vitro, but the application of these vector systems is presently limited by their low transduction efficiency in vivo. In contrast, a vector derived from a recombinant adenovirus can restore 10%-80% of normal hepatic PAH activity into PAH-deficient mice, which completely normalizes serum phenylalanine levels. This treatment is transient and cannot be effectively re-administered due to the presence of neutralizing antibodies directed against the recombinant adenoviral vector. However, these findings suggest that PKU can be completely corrected by somatic gene therapy, and provide some direction for the future development of adenoviral vectors.
Language of Publication: English
Unique Identifier: 96426308

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MeSH Heading (Major): Gene Therapy|*; Phenylketonuria|*TH
MeSH Heading: Adenoviridae|GE/IM; Animal; DNA, Recombinant|GE; Genetic Vectors|IM; Human; Liver|CY; Retroviridae|GE

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0340-6199
Country of Publication: GERMANY

Record 55 from database: MEDLINE
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Title: Relationship between genotype and phenotype in monogenic diseases: relevance to polygenic diseases.
Author: Summers KM
Address: Department of Medicine, University of Queensland, Prince Charles Hospital, Australia.
Source: Hum Mutat, 1996, 7:4, 283-93
Abstract: Since the early descriptions of sickle cell anemia, it has been clear that genotype at a single locus rarely completely predicts phenotype. This paper reviews explanations for phenotypic variability in some monogenic diseases. In cystic fibrosis, there is strong correlation between genotype and pancreatic phenotype but only weak association with respiratory phenotype, possibly due to differential inheritance of alleles at loci controlling susceptibility to respiratory infection. In addition, disease mutations have been shown to have more or less severe effect, depending on other variation within the cystic fibrosis gene. In phenylketonuria, genotype at the phenylalanine hydroxylase locus appears to explain the biochemical phenotype, but not the intellectual status. There may be genetically determined variation in flux through the minor metabolic pathways for phenylalanine, influencing levels of alternative metabolites involved in mental development. Phenotypic discordance in sickle cell anemia and beta-thalassemia has been associated with the co-inheritance of genes for hereditary persistence of fetal hemoglobin. A mouse locus has been identified that influences tumour number in mice with the multiple intestinal neoplasia gene. Understanding of the genetic interactions that determine phenotype in apparently monogenic diseases should lead to clarification of the role of different genes in polygenic diseases with complex inheritance patterns, as well as enhancing the ability to predict the outcome of a disease mutation.
Language of Publication: English
Unique Identifier: 96303698

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MeSH Heading (Major): Genotype|*; Hereditary Diseases|*GE; Phenotype|*
MeSH Heading: beta-Thalassemia|GE; Adenomatous Polyposis Coli|GE; Anemia, Sickle Cell|GE; Animal; Cystic Fibrosis|GE; Disease Models, Animal; Hemoglobinopathies|GE; Human; Metabolism, Inborn Errors|GE; Mice; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1059-7794
Country of Publication: UNITED STATES

Record 56 from database: MEDLINE
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Title: Use of aspartame in pregnancy.
Author: Sturtevant FM
Address
Source: Int J Fertil, 1985, 30:1, 85-7
Abstract: The low-calorie sweetening agent, aspartame, is broken down in the small intestine into three moieties: aspartic acid, methanol and phenylalanine. Acute loading studies have been performed in human beings who received up to six times the 99th percentile of the projected daily intake (6 X 34 = 200 mg/kg). No evidence of risk to the fetus was developed. Aspartate does not readily cross the placenta. Small elevations of blood methanol following such abuse doses of aspartame did not lead to measurable increases of blood formic acid, which is the product responsible for the acidosis and ocular toxicity in methanol poisoning. Phenylalanine is concentrated on the fetal side of the placenta. Aspartame in abuse doses up to 200 mg/kg in normal subjects, or to 100 mg/kg in PKU heterozygotes, did not raise blood phenylalanine levels to the range generally accepted to be associated with mental retardation in the offspring. It is concluded that, under foreseeable conditions of use, aspartame poses no risk for use in pregnancy.
Language of Publication: English
Unique Identifier: 85260289

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MeSH Heading (Major): Aspartame|ME/*PD; Dipeptides|*PD; Fetus|*DE; Pregnancy|*DE
MeSH Heading: Alcohol, Methyl|ME; Aspartic Acid|ME; Digestion; Female; Human; Phenylalanine|ME

Publication Type: JOURNAL ARTICLE; REVIEW
ISSN: 0020-725X
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine); 56-84-8 (Aspartic Acid); 67-56-1 (Alcohol, Methyl)

Record 57 from database: MEDLINE
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Title: Defects of tetrahydrobiopterin synthesis and their possible relationship to a disorder of purine metabolism (the Lesch-Nyhan syndrome).
Author: Watts RW
Address
Source: Adv Enzyme Regul, 1985, 23:, 25-58
Abstract: The metabolic pathways of pterin de novo synthesis, interconversion and salvage which lead to the tetrahydrobiopterin cofactor of phenylalanine 4-monooxygenase, tyrosine 2-monooxygenase and tryptophan 5-monooxygenase are reviewed and data on the enzymes which catalyze the individual steps are presented. Analogies drawn between the inborn errors of tetrahydrobiopterin production and the Lesch-Nyhan syndrome, in which purine salvage is deficient, are used as a basis for the hypothesis that the neurological manifestations of the Lesch-Nyhan syndrome are due to neurotransmitter imbalance which stems from an imbalance of the aromatic amino acid monooxygenase activities which are themselves due to impaired pterin biosynthesis. The latter arises because, in the absence of the hypoxanthine phosphoribosyltransferase catalyzed purine salvage pathway, the supply of GTP for the GTP cyclohydrolase reaction, which is the first reaction on the pterin de novo synthesis pathway, is reduced. It is proposed that the different aromatic amino acid monooxygenases are differentially affected by this constrained pterin production. The activities of those most directly related to the quantal production of the cerebral neurotransmitters dopamine, norepinephrine and 5-hydroxytryptamine are affected whereas liver phenylalanine 4-monooxygenase activity is not overtly impaired. The results of different lines of research which support this concept are cited, as is direct evidence for a selective reduction of dopamine production in the basal ganglia of patients with the Lesch-Nyhan syndrome. It is proposed that lack of GMP for functions, other than its role in pterin de novo synthesis, accounts for the features of the Lesch-Nyhan syndrome which do not occur when only tetrahydrobiopterin production is deficient as in the inborn errors of tetrahydrobiopterin synthesis.
Language of Publication: English
Unique Identifier: 86073655

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MeSH Heading (Major): Biopterin|AA/*BI; Lesch-Nyhan Syndrome|*ME; Pteridines|*BI; Purines|*ME
MeSH Heading: Brain|ME; Dopamine|ME; GTP Cyclohydrolase|ME; Human; Hypoxanthine Phosphoribosyltransferase|DF; Nervous System Diseases|ME; Neurotransmitters|ME; Pterins|ME/UR

Publication Type: JOURNAL ARTICLE; REVIEW
ISSN: 0065-2571
Country of Publication: ENGLAND
CAS Registry/EC Number: EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase); EC 3.5.4.- (erythro-dihydrobiopterin triphosphate synthetase); EC 3.5.4.16 (GTP Cyclohydrolase); 0 (Neurotransmitters); 0 (Pteridines); 0 (Pterins); 0 (Purines); 17528-72-2 (5,6,7,8-tetrahydrobiopterin); 22150-76-1 (Biopterin); 51-61-6 (Dopamine)

Record 58 from database: MEDLINE
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Title: Dysfunction of CFTR bearing the delta F508 mutation.
Author: Welsh MJ; Denning GM; Ostedgaard LS; Anderson MP
Address: Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242.
Source: J Cell Sci Suppl, 1993, 17:, 235-9
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in patients with cystic fibrosis (CF). The most common CF-associated mutation is deletion of phenylalanine at residue 508, CFTR delta F508. When expressed in heterologous cells, CFTR bearing the delta F508 mutation fails to progress through the normal biosynthetic pathway and fails to traffic to the plasma membrane. As a result, CFTR delta F508 is mislocalized and is not present in the apical membrane of primary cultures of airway epithelia. Consequently, the apical membrane of CF airway epithelia is Cl- -impermeable, a defect that probably contributes to the pathogenesis of the disease.
Language of Publication: English
Unique Identifier: 94193834

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MeSH Heading (Major): Cystic Fibrosis|ET/*GE/*ME; Membrane Proteins|CH/*GE/*ME
MeSH Heading: Cell Membrane|ME; Chloride Channels|GE/ME; Epithelium|ME; Glycosylation; Human; Molecular Structure; Protein Processing, Post-Translational; Respiratory System|ME; Sequence Deletion; Temperature

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0269-3518
Country of Publication: ENGLAND
CAS Registry/EC Number: 0 (Chloride Channels); 0 (Membrane Proteins); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)

Record 59 from database: MEDLINE

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Title: The 'cerebral diabetes' paradigm for unipolar depression.
Author: Newman JC; Holden RJ
Address: Shellharbour Hospital, Illawarra Area Health Service, NSW, Australia.
Source: Med Hypotheses, 1993 Nov, 41:5, 391-408
Abstract: Unipolar depression, alcoholism and suicide have become more common over the past decades. Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci for insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. Since TH and the insulin receptor require phosphorylation by protein kinases, then a defect of the h-ras-oncogene or its products (p21) could disorder both these systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. This could lead not only to a predisposition to depression ('trait markers') but to neurotoxic damage, predisposed by inadequate cytosol Mg2+ levels of hypometabolism. Tyrosine, tryptophan and phenylalanine hydroxylases all require tetrahydrobiopterin (BH4) which allosterically regulates its own activity as well as that of these enzymes. Anything which impairs this cofactor could lead to overt depression in predisposed individuals, and the heterocyclic amines are being increasingly implicated. These substances are derived from fried and broiled meats, azo food dyes, soft drinks and hard candies, but particularly from cigarette and petroleum fumes. The heterocyclic amines can inhibit aromatic-l-amino-acid-decarboxylase (AADC) as well as the hydroxylases reversibly, but BH4 is inhibited noncompetitively. Thus, susceptible individuals (those with inherited defective protein kinase phosphorylation) might be 'tipped over' by chronic exposure to these neurotoxins. The rising incidence of unipolar depression-associated morbidity could be significantly linked to increasing levels of heterocyclic amines in the developed nations.
Language of Publication: English
Unique Identifier: 94195118

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MeSH Heading (Major): Depressive Disorder|*ET/GE/ME; Models, Biological|*
MeSH Heading: Amines|AE; Animal; Aromatic Amino Acid Decarboxylases|ME; Brain|ME; Diabetes Mellitus|ME; Glucose|ME; Human; Insulin|ME; Tyramine|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0306-9877
Country of Publication: ENGLAND
CAS Registry/EC Number: EC 4.1.1.28 (Aromatic Amino Acid Decarboxylases); 0 (Amines); 11061-68-0 (Insulin); 50-99-7 (Glucose); 51-67-2 (Tyramine)

Record 60 from database: MEDLINE
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Title: Congenital adrenal hyperplasia (CAH)--the place for prenatal treatment and neonatal screening.
Author: Kelnar CJ
Address: Department of Child Life and Health, University of Edinburgh, UK.
Source: Early Hum Dev, 1993 Dec 15, 35:2, 81-90
Abstract: What are the respective places for prenatal treatment and neonatal screening in 21 hydroxylase deficiency, (21OHD) CAH? Current diagnostic procedures for 21OHD CAH do not prevent potential or actual morbidity and mortality from salt wasting and hypoglycaemia, ambiguous genitalia and late diagnosis. Presentation is with life-threatening illness or virilisation with long-term physical, psychological and psychosexual sequelae. Screening the whole newborn population would add only a very small additional unit cost in the screening laboratory already measuring TSH and phenylalanine. There are still few data on which to base an assessment of the efficacy of neonatal screening in reducing morbidity and mortality. Screening should now be adopted on a regional, or national, basis to assess both efficacy and cost-effectiveness. Although more (uncontrolled) data are now available concerning prenatal dexamethasone therapy, the degree of benefit in terms of reduced virilisation in relation to potentially significant maternal side effects is unclear and possible long term childhood side effects have not been studied. At present, therefore, there is insufficient evidence regarding the safety of mother and fetus to recommend the general use of dexamethasone outwith the context of controlled scientific studies. There is an urgent need for prospective controlled studies to be undertaken which would, in time, resolve both questions.
Language of Publication: English
Unique Identifier: 94192470

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MeSH Heading (Major): Adrenal Hyperplasia, Congenital|*DI/*DT/EM/GE; Neonatal Screening|*; Prenatal Diagnosis|*
MeSH Heading: Dexamethasone|TU; Female; Human; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0378-3782
Country of Publication: IRELAND
CAS Registry/EC Number: 50-02-2 (Dexamethasone)

Record 61 from database: MEDLINE
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Title: Mechanical models of pseudopod formation.
Author: Skalak R; Skierczynski BA; Wung SL; Chien S; Usami S
Address: Institute of Biomedical Engineering, University of California-San Diego, La Jolla 92093-0412.
Source: Blood Cells, 1993, 19:2, 389-97; discussion 398-9
Abstract: The active locomotion of polymorphonuclear leukocytes into a glass pipette has been recently reported using formyl-methionyl-leucyl-phenylalanine (fMLP) as a chemoattractant. The frontal portion of the leukocyte appears clear and free of granules as observed in pseudopod formation. Three possible mechanisms for pseudopod formation are considered: (1) pressure-flow generated by actin-myosin contraction at the rear of the cell or at the base of the pseudopod; (2) osmotic pressure generated at the cell membrane, interior to the cell; and (3) actin polymerization of the cell membrane at the leading edge of the pseudopod. Experimental data on the movement of F-actin toward the rear of the cell, away from the front, favors polymerization of G-actin to F-actin at the leading edge. The active role of osmotic pressure and contraction at the base of the pseudopod are possible but not yet proven.
Language of Publication: English
Unique Identifier: 94146374

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MeSH Heading (Major): Cell Movement|*PH; Chemotaxis, Leukocyte|*; Models, Biological|*; Neutrophils|*PH
MeSH Heading: Actins|ME/PH; Animal; Cell Membrane|PH; Human; Mathematics; Myosin|ME/PH; N-Formylmethionine Leucyl-Phenylalanine|PD

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0340-4684
Country of Publication: GERMANY
CAS Registry/EC Number: 0 (Actins); 0 (Myosin); 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)

Record 62 from database: MEDLINE
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Title: The systemic administration of intravenous melphalan.
Author: Sarosy G; Leyland-Jones B; Soochan P; Cheson BD
Address: Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892.
Source: J Clin Oncol, 1988 Nov, 6:11, 1768-82
Abstract: Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.
Language of Publication: English
Unique Identifier: 89036319

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MeSH Heading (Major): Melphalan|*AD/AE/PK; Neoplasms|*DT
MeSH Heading: Administration, Oral; Body Water|ME; Bone Marrow|DE; Chemistry; Clinical Trials; Human; Infusions, Intravenous

Publication Type: CLINICAL TRIAL; JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0732-183X
Country of Publication: UNITED STATES
CAS Registry/EC Number: 148-82-3 (Melphalan)

Record 63 from database: MEDLINE
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Title: Trace amines and Tourette's syndrome.
Author: Baker GB; Bornstein RA; Yeragani VK
Address: Department of Psychiatry, University of Alberta, Edmonton, Canada.
Source: Neurochem Res, 1993 Sep, 18:9, 951-6
Abstract: There has been considerable interest in recent years in possible neurochemical abnormalities in Tourette's Syndrome (TS). In studies combining neuropsychological and neurochemical measurements, we have investigated the possible roles of trace amines in this disorder. Urinary levels of free beta-phenylethylamine (PEA) and plasma levels of its precursor amino acid phenylalanine were decreased in TS patients when compared to values in normal children. These urinary PEA levels in TS patients were inversely related to several scores from the Tourette's Syndrome Global Scale (TSGS). Further investigation of the group of subjects with low urinary PEA indicated that they also had low levels of MHPG, normetanephrine, 5-HT and m- and p-tyramine. Patients with low PEA were also compared on an extensive battery of neuropsychological measures and observed to perform significantly worse than TS patients with normal urinary PEA levels. Biochemical measurements also suggest a possible abnormality in tryptamine turnover in TS since urinary levels of indole-3-acetic acid (IAA; the acid metabolite of tryptamine) are significantly lower in TS patients than in normal controls.
Language of Publication: English
Unique Identifier: 94050343

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MeSH Heading (Major): Biogenic Amines|*ME; Tourette Syndrome|ET/*ME
MeSH Heading: Human; Molecular Structure; Phenethylamines|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Tryptamines|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0364-3190
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Biogenic Amines); 0 (Phenethylamines); 0 (Tryptamines); 61-54-1 (tryptamine); 64-04-0 (phenethylamine)

Record 64 from database: MEDLINE
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Title: Unraveling prion diseases through molecular genetics.
Author: Westaway D; Carlson GA; Prusiner SB
Address
Source: Trends Neurosci, 1989 Jun, 12:6, 221-7
Abstract: Prions are transmissible pathogens that cause degenerative diseases in humans and animals. Unique attributes of prion diseases include infectious, sporadic and genetic manifestations, as well as progression to death, all in the absence of a detectable immune response. Prions are resistant to chemical procedures that modify or destroy nucleic acids and are composed largely of a protein, designated PrPSc. Molecular cloning of a cognate cDNA established a cellular host origin for PrPSc protein and a convergence with the genetics of host susceptibility. The murine PrP gene is linked to the Prn-i gene which determines incubation times in experimental scrapie. Mice with long incubation times have unusual PrP alleles encoding phenylalanine and valine at codons 108 and 189. Moreover, the ataxic form of Gerstmann-Sträussler syndrome (a rare human neurodegenerative disorder) has been defined as an autosomal dominant disorder with a PrP mis-sense mutation at codon 102 linked to the predisposition locus. These studies argue that amino acid substitutions in 'PrP' genes may modulate initiation and development of prion diseases.
Language of Publication: English
Unique Identifier: 89318519

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MeSH Heading (Major): Nervous System Diseases|*MI; Prions|*GE
MeSH Heading: Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0166-2236
Country of Publication: ENGLAND
CAS Registry/EC Number: 0 (Prions)

Record 65 from database: MEDLINE
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Title: The control of aromatic amino acid catabolism and its relationship to neurotransmitter amine synthesis.
Author: Pogson CI; Knowles RG; Salter M
Address: Biochemical Sciences, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Source: Crit Rev Neurobiol, 1989, 5:1, 29-64
Abstract: The aromatic amino acids are, inter alia, substrates for the synthesis of important neurotransmitters. Although the factors controlling the synthesis of these transmitters are not fully understood, there is evidence that the concentrations, both relative and absolute, of the precursor amino acids in the blood are of some significance. The article reviews the biochemical pathways involved in tryptophan, phenylalanine, and tyrosine metabolism in liver, brain, and other tissues and discusses (1) the major regulatory events in the maintenance of blood concentrations and (2) the effects of diet, load dosing, hormones, and other circulating substances on the fate of the amino acids and on events in the central nervous system.
Language of Publication: English
Unique Identifier: 89354612

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MeSH Heading (Major): Amino Acids|*ME; Biogenic Amines|*BI; Neurotransmitters|*BI
MeSH Heading: Animal; Brain|DE/ME; Human; Liver|ME; Phenylalanine|ME/PD; Tryptophan|ME/PD; Tyrosine|ME/PD

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0892-0915
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amino Acids); 0 (Neurotransmitters); 3617-44-5 (Phenylalanine); 55520-40-6 (Tyrosine); 6912-86-3 (Tryptophan)

Record 66 from database: MEDLINE
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Title: Cytosolic free Ca2+ signals in single adherent human neutrophils: generation and functional role.
Author: Jaconi ME; Theler JM; Schlegel W; Lew PD
Address: Division of Infectious Diseases, Geneva University Hospital, Switzerland.
Source: Eur J Pediatr, 1993, 152 Suppl 1:, S26-32
Abstract: To study the role of cytosolic free calcium, [Ca2+]i, in cell activation, in particular during adhesion and movement on a surface in response to chemotactic peptide stimulation and during phagocytosis, we monitored [Ca2+]i in single human neutrophils. The neutrophils were loaded with fura-2 and allowed to adhere to albumin-coated glass coverslips. [Ca2+]i was monitored with a dual excitation microfluorimeter. Half of the cells showed spontaneous [Ca2+]i transients that lasted up to 15 min with an amplitude averaging 77 +/- 10 nM above basal levels (mean basal value of 110 +/- 20 nM) and a mean duration of 28 +/- 5 s. These repetitive [Ca2+]i elevations depended on the continuous presence of extracellular Ca2+ and could be dissociated from those triggered by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP). Cell morphology was monitored in parallel by recording fluorescent images with a high sensitivity charge coupled device (CCD) camera. The majority of the cells studied showed visible changes in shape which started either before or at the same time as the onset of the [Ca2+]i transients. Removal of extracellular Ca2+ abolished [Ca2+]i transients without impairing cell movement and spreading. Blockade of adherence and cell movement with cytochalasin B markedly inhibited [Ca2+]i transients. Monoclonal antibodies directed against the leucocyte integrin CR3 (CD11b/CD18 alpha m beta 2) blocked adherence, spreading and most of the [Ca2+]i activity. Total [Ca2+]i activity was assessed during phagocytosis of C3bi-opsonized yeast particles and correlated with fusion of secondary granules with the phagosomal membrane (P-L fusion).(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 93307344

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MeSH Heading (Major): Calcium|*PH; Neutrophils|CY/*PH
MeSH Heading: Cell Adhesion; Cell Movement; Cytosol; Fura-2|FURA 02; Human; Lysosomes|PH; Macrophage-1 Antigen|PH; N-Formylmethionine Leucyl-Phenylalanine|FORMYLMETHIONINELEUCYLPHENYLALANINE N; Phagocytosis; Phagosomes|PH; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0340-6199
Country of Publication: GERMANY
CAS Registry/EC Number: 0 (Macrophage-1 Antigen); 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine); 7440-70-2 (Calcium); 96314-98-6 (Fura-2)

Record 67 from database: MEDLINE
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Title: Nutrition in the management of inborn errors of metabolism [published erratum appears in Clin Lab Med 1993 Dec;13(4):following table of contents]
Author: Dashman T; Sansaricq C
Address: Department of Pediatrics, New York University Medical Center, New York.
Source: Clin Lab Med, 1993 Jun, 13:2, 407-32
Abstract: The determination of specific nutrients is important in the diagnosis of several inborn errors of metabolism. Phenylketonuria (PKU) is a well-known example. In this case, the nutrient, phenylalanine, is assayed to confirm a diagnosis and is routinely measured to monitor therapy, which consists of a diet low in this particular amino acid. Although many of the described inborn errors of metabolism are uncommon, or even rare, in occurrence, the laboratory plays an essential role in the diagnosis and management of these diseases.
Language of Publication: English
Unique Identifier: 93306914

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MeSH Heading (Major): Metabolism, Inborn Errors|*DH; Nutrition|*
MeSH Heading: Human; Metabolic Detoxication, Drug

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0272-2712
Country of Publication: UNITED STATES

Record 68 from database: MEDLINE
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Title: Mutagenic activity of peptides and the artificial sweetener aspartame after nitrosation.
Author: Shephard SE; Wakabayashi K; Nagao M
Address: Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Source: Food Chem Toxicol, 1993 May, 31:5, 323-9
Abstract: Naturally occurring dipeptides, cholecystokinine (CCK, a tetrapeptide hormone) and the artificial sweetener aspartame were nitrosated for 10-30 min with 40 mM-nitrite (pH 3.5, 37 degrees C), and the resultant products examined for mutagenicity in Salmonella typhimurium TA100. Specific mutagenicities (net revertants per mumol precursor) spanned four orders of magnitude, with CCK being the most potent precursor (4700 revertants/mumol) followed by tryptophyl-tryptophan (Trp-Trp; 1000 revertants/mumol). Aspartame and glycyl-Trp (Gly-Trp) had intermediate activity (300 revertants/mumol), while Gly-Gly and methionyl-methionine were only weakly mutagenic (20 and 12 revertants/mumol, respectively). The dipeptides of aspartic acid, phenylalanine and tyrosine had no detectable mutagenicity (limits of detection 0.5, 40 and 5 revertants/mumol, respectively). Kinetic studies with aspartame and Gly-Trp suggested that the mutagenic products arose primarily from nitrosation of the primary amine rather than the amide or indole group. The mutagenicities of nitrosated aspartame and Gly-Trp were higher in TA100 than in TA98, and higher without than with enzymatic activation (S-9 mix) in both strains. The time-course study of Trp-Trp nitrosation showed the production of at least two mutagens: a potent but unstable mutagenicity was seen at very short nitrosation times and a more stable but weaker effect was obtained after more than 60 min of nitrosation. Not only the absolute specific mutagenicity but also the nitrite dependence of the nitrosation reaction and the stability of the nitroso product must be taken into account in determining the risk posed by endogenous nitrosation of foods in the human stomach. Under stomach conditions, nitrosation of the side-chains of certain Trp peptides would be expected to contribute more to the endogenous burden of nitrosated products than nitrosation of aspartame or Gly peptides.
Language of Publication: English
Unique Identifier: 93279602

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MeSH Heading (Major): Aspartame|*TO; Dipeptides|*TO
MeSH Heading: Animal; Comparative Study; Human; Mutagenicity Tests; Nitrosation; Salmonella typhimurium|DE; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0278-6915
Country of Publication: ENGLAND
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame)

Record 69 from database: MEDLINE
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Title: Inhibition of in vitro platelet aggregation and release and fibrinolysis.
Author: Narayanan S
Address: Department of Pathology, New York Medical College-Metropolitan Hospital Center, NY 10029.
Source: Ann Clin Lab Sci, 1989 Jul-Aug, 19:4, 260-5
Abstract: Inhibition of in vitro platelet aggregation and release of contents of platelet granules is necessary in order to assess accurately platelet activation in vivo. This can be accomplished by using a variety of inhibitors added to blood collection containers. An additive mixture of citrate, theophylline, adenosine, and dipyridamole (CTAD) provides a practical alternative to a mixture of acid citrate dextrose (ACD), acetylsalicylic acid (aspirin), and prostaglandin E1 (PGE1) because of the stability problems associated with PGE1. Inhibition of in vitro fibrinolysis is essential for the accurate measurement of fibrin degradation products (FDP). This can be accomplished by using a mixture of thrombin, soybean trypsin, or aprotinin into which blood is collected. However, in patients receiving heparin, the fibrinolysis inhibitor mixture is ineffective unless it is supplemented with reptilase. With increasing use of recombinant tissue-type plasminogen activator therapy (rt-PA), an inhibitor such as D-phenylalanine-proline-arginine-chloromethylketone (PPACK) used as a blood collection additive is superior to a conventional protease inhibitor, such as aprotinin.
Language of Publication: English
Unique Identifier: 89334291

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MeSH Heading (Major): Fibrinolysis|*DE; Platelet Aggregation|*DE
MeSH Heading: Alteplase|AI; Blood Platelets|ME; Fibrin Fibrinogen Degradation Products|AN; Human; In Vitro; Platelet Aggregation Inhibitors|PD; Recombinant Proteins|AI; Specimen Handling

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0091-7370
Country of Publication: UNITED STATES
CAS Registry/EC Number: EC 3.4.21.- (Alteplase); 0 (Fibrin Fibrinogen Degradation Products); 0 (Platelet Aggregation Inhibitors); 0 (Recombinant Proteins)

Record 70 from database: MEDLINE
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Title: Lysosomal degradation of microinjected proteins.
Author: Dice JF; Chiang HL
Address: Department of Physiology, Tufts University School of Medicine, Boston, MA 02111.
Source: Revis Biol Celular, 1989, 20:, 13-33
Abstract: In this article we summarize evidence for a pathway by which cytosolic proteins can be selectively taken up and degraded within lysosomes. Serum deprivation of cells in culture activates this pathway, and only proteins that contain peptide sequences related to KFERQ (lysine, phenylalanine, glutamic acid, arginine, glutamine) are degraded at enhanced rates. Approximately 30% of intracellular proteins contain such peptide sequences, and we speculate about the physiological relevance of the selective degradation of these proteins in response to serum withdrawal. Several rat tissues also contain proteins with peptide sequences related to KFERQ, and the amount of these proteins is reduced in response to starvation. Finally, we present recent results suggesting that this selective uptake of cytosolic proteins by lysosomes is not through classical macroautophagic pathways. Instead, the selective uptake may be similar to other protein sorting pathways such as protein translocation through the endoplasmic reticulum or protein import into mitochondria.
Language of Publication: English
Unique Identifier: 90272995

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MeSH Heading (Major): Lysosomes|*ME; Proteins|*ME
MeSH Heading: Amino Acid Sequence; Animal; Autophagocytosis; Cytoplasm|ME; Human; Microinjections; Molecular Sequence Data; Ribonucleases|AD/ME; Structure-Activity Relationship; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0213-7119
Country of Publication: SPAIN
CAS Registry/EC Number: EC 3.1.- (Ribonucleases)

Record 71 from database: MEDLINE
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Title: Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. Medical Research Council Working Party on Phenylketonuria.
Author: Anonymous
Address
Source: BMJ, 1993 Jan 9, 306:6870, 115-9
Abstract: Efficient neonatal screening for phenylketonuria and the availability of complex diets for lifelong use have virtually eliminated severe mental handicap from the disease. Nevertheless, there remains a high risk of fetal damage in offspring of women with the disease, and the possibility that the diets themselves may be harmful cannot be excluded. Search for a preventive treatment for the disease has been greatly aided by advances in molecular genetics. For example, in mice modified liver cells have been implanted, which have not only corrected the phenylalanine defect but have remained healthy for the normal life span of the animal. Overall, however, prevention and treatment have not progressed as quickly as was hoped, and research and development must be pursued vigorously to take account of contemporary perceptions of the disorder.
Language of Publication: English
Unique Identifier: 93169184

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MeSH Heading (Major): Phenylalanine Hydroxylase|*DF/*GE; Phenylketonuria|CO/*GE/TH
MeSH Heading: Adolescence; Adult; Animal; Central Nervous System Diseases|ET; Child; Female; Great Britain; Health Services Needs and Demand; Human; Mice; Phenylketonuria, Maternal|CO; Pregnancy

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0959-8138
Country of Publication: ENGLAND
CAS Registry/EC Number: EC 1.14.16.1 (Phenylalanine Hydroxylase)

Record 72 from database: MEDLINE
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Title: Clinical hyperthermia and chemotherapy.
Author: Storm FK
Address: Division of Surgical Oncology, University of Wisconsin Medical School, Madison.
Source: Radiol Clin North Am, 1989 May, 27:3, 621-7
Abstract: Hyperthermia may act additively or synergistically with a majority of clinically useful chemotherapeutic agents in vitro. In some cases enhanced responses are essentially linear at temperatures from 39 to 43 degrees C (thiotepa, the nitrosoureas, cisplatin), while other drugs become more effective only at 42 to 43 degrees (doxorubicin, bleomycin, amphotericin B). Synergism has been observed in vivo with methotrexate, cyclophosphamide, the nitrosoureas, doxorubicin, bleomycin, and cisplatin. Optimum enhancement occurs when heat and drug are given simultaneously. Clinical studies employing WBH at 41 to 41.8 degrees C have shown evidence of potential usefulness, but have been limited by high toxicity and a low benefit-to-risk ratio. Regional perfusion of metastatic melanoma of the extremity treated with L-phenylalanine mustard at 40 to 41 degrees C was significantly better than when treated with the drug alone, but some investigations suggest that heat alone may be just as effective. Localized hyperthermia combined with nearly all the standard types and doses of single and combination agents has shown objective responses in about one third of patients treated, without evidence of increased drug toxicity by either the IV or IA route. Responses appear to be thermal-dose related. Maximum enhancement appears at about 40 to 43 degrees C and prior drug resistance does not appear to confer heat resistance. The lack of enhanced drug toxicity with loco-regional hyperthermia with potential improvement in response of advanced disease suggests that thermochemotherapy is a viable and important option to drug treatment alone. Further in vitro, in vivo, and clinical studies are needed to increase our understanding of drug-heat interactions for the optimization of therapy.
Language of Publication: English
Unique Identifier: 89185437

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MeSH Heading (Major): Antineoplastic Agents|*TU; Hyperthermia, Induced|*; Neoplasms|DT/*TH
MeSH Heading: Animal; Combined Modality Therapy; Human; Neoplasms, Experimental|DT/TH

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0033-8389
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Antineoplastic Agents)

Record 73 from database: MEDLINE
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Title: Cystic fibrosis gene.
Author: Harris A
Address: Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Source: Br Med Bull, 1992 Oct, 48:4, 738-53
Abstract: The cystic fibrosis gene, located at 7q31, spans about 230 kb of genomic DNA and contains 27 exons. The cDNA of 6.2kb would predict an 1480 amino acid protein, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR has a high degree of homology with members of the ABC-transporter super family. The predicted protein structure consists of two membrane-spanning domains, each of 6 sub-units, anchoring CFTR in the apical membrane of specialized epithelial cells, 2 nucleotide binding folds (NBF) and a regulatory (R) domain. Disease-associated mutations in the CF gene are mainly clustered in the nucleotide-binding folds. The most common mutation, occurring in 70% of CF genes in Northern Europe and North America, is the deletion of amino acid phenylalanine at position 508 in the first NBF (ie delta F508).
Language of Publication: English
Unique Identifier: 93091923

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MeSH Heading (Major): Chromosomes, Human, Pair 7|*; Cystic Fibrosis|*GE; Genes|*; Membrane Proteins|*GE; Mutation|*GE
MeSH Heading: Exons; Genotype; Human; Phenotype

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0007-1420
Country of Publication: ENGLAND
CAS Registry/EC Number: 0 (Membrane Proteins); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)

Record 74 from database: MEDLINE
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Title: CFTR!
Author: Fuller CM; Benos DJ
Address: Department of Physiology and Biophysics, University of Alabama 35294.
Source: Am J Physiol, 1992 Aug, 263:2 Pt 1, C267-86
Abstract: Cystic fibrosis (CF) is a fatal genetic disease primarily affecting Caucasians, although cases have been reported from other ethnic groups. CF has a complex etiology, but it is chiefly a disease of electrolyte transport and is characterized by defects in fluid secretion by several epithelia, including the sweat duct, exocrine pancreas, and the pulmonary airways. The link between CF and a defect in cAMP-mediated Cl- transport in secretory epithelia was established in the early 1980s. Since then, numerous electrophysiological studies have focused on the characterization and regulation of individual Cl- channels underlying the macroscopic Cl- currents of secretory epithelia in the airways, sweat ducts, and gut. In this review the results of these studies in the light of current knowledge of the function of the CF gene product, the CF transmembrane conductance regulator (CFTR) protein, will be analyzed. The CFTR protein is a member of a family of ATP-binding proteins that act as unidirectional solute pumps. These proteins are membrane spanning, are found in both prokaryotic and eukaryotic cells, and have two ATP-binding domains. The family includes the p-glycoproteins that are involved with the expression of multidrug resistance in certain tumor cells. The majority of CF chromosomes (70%) have a single codon deletion that translates to a missing phenylalanine residue at position 508 (delta F508) of the protein. Unique for this family of proteins, the CFTR protein possesses an additional highly charged domain (the R domain) containing several consensus polypeptide sequences for kinase phosphorylation. Although CFTR bears structural resemblance to this family of ATP-dependent pumps, overexpression of the protein in a variety of different cell types is associated with the appearence of a cAMP-sensitive Cl- channel. We critically examine current information concerning the structure-function relationships of the CFTR protein obtained from both electrophysiological and biochemical approaches. We also summarize recent evidence suggesting that the CFTR protein may act as a pump and a channel, a hypothesis in keeping with the multifaceted nature of the disease.
Language of Publication: English
Unique Identifier: 92384271

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MeSH Heading (Major): Membrane Proteins|*/GE/ME/PH
MeSH Heading: Adenosine Triphosphate|ME; Biological Transport; Cystic Fibrosis|ME/TH; Human; Ions; Mutation; Peptide Mapping; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0002-9513
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Chloride Channels); 0 (Ions); 0 (Membrane Proteins); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 56-65-5 (Adenosine Triphosphate)

Record 75 from database: MEDLINE
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Title: Guidelines for the treatment of vitiligo.
Author: Antoniou C; Katsambas A
Address: University of Athens, School of Medicine, Department of Dermatology, Greece.
Source: Drugs, 1992 Apr, 43:4, 490-8
Abstract: At present, there is no universally effective drug for vitiligo therapy; there are, however, various therapeutic modalities that may be beneficial. Therapeutic regimens used to treat vitiligo include psoralens and ultraviolet A light (PUVA), topical corticosteroids, fluorouracil locally applied with skin abrasion, a variety of surgical techniques to transplant autologous melanocytes from pigmented skin to nonpigmenting areas, a new photochemotherapeutic regimen using oral khellin with UVA phototherapy, and a recently proposed treatment with oral phenylalanine in combination with UVA exposure. PUVA and topical corticosteroids are the 2 most frequently used modalities. The use of effective sunscreens with a high sun protection factor (SPF) is of help in preventing the vitiliginous areas from burning and normal skin from becoming tanned. Cosmetic camouflage is also useful to disguise the white areas of skin. Finally, depigmentation should be considered in patients with greater than 50% cutaneous involvement who fail to respond or are unwilling to undergo treatment. The selection of patients for therapy should take into consideration the patient's motivation, the psychological impact of the disease and the clinical presentation of vitiligo, and should weigh the risks and benefits of prolonged therapy.
Language of Publication: English
Unique Identifier: 92306804

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MeSH Heading (Major): Vitiligo|DT/SU/*TH
MeSH Heading: Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0012-6667
Country of Publication: NEW ZEALAND

Record 76 from database: MEDLINE
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Title: Immunonutrition: role of sulfur amino acids, related amino acids, and polyamines.
Author: Grimble RF; Grimble GK
Address: Institute of Human Nutrition, University of Southampton, UK.
Source: Nutrition, 1998 Jul-Aug, 14:7-8, 605-10
Abstract: Pro-inflammatory cytokines mediate widespread changes in protein metabolism. Amino acids released from peripheral tissues fulfill a number of functions. They act as substrate for acute phase protein and immunoglobulin synthesis and, together with polyamines, in the replication of immune cells. Demands for specific amino acids may outstrip the supply from endogenous sources. A number of strands of evidence suggest that sulphur amino acids, and amino acids that are metabolically related to them, may be required in increased amounts. Protein deficiency impairs the acute phase response. However, sulfur amino acid insufficiency compromises glutathione synthesis, to a greater extent than hepatic protein synthesis, in the presence and absence of an inflammatory stimulus. The resulting effect may be compromised antioxidant defences. Functioning of T cells is dependent on intracellular glutathione concentrations and may also be affected by sulphur amino acid insufficiency. It has been suggested that the increased N excretion, which occurs during the immune response, is a reflection of a relative imbalance in the profile of amino acids released from peripheral tissues and the requirements imposed by the synthesis of substances involved in the acute phase response. Phenylalanine, tyrosine, tryptophan serine, and cysteine are released in amounts closest to requirements. Polyamine synthesis may be important for the fidelity of the enhanced level DNA transcription and RNA translation that occurs in response to infection and during tissue repair, gut growth after surgery, and in gut barrier functions. Although synthesized de novo from ornithine, arginine and S-adenosyl methionine (SAM), substantial recycling is a key feature of polyamine metabolism. The recycling may be a reflection of the need to maintain adequate tissue SAM during periods of rapid cell growth. During an immune/inflammatory response the combination of enhanced utilization of cysteine for glutathione synthesis and cell replication may lead to depletion of cellular SAM. A relatively small addition of polyamines to the diet may improve gut-associated aspects of the hosts' antibacterial defenses.
Language of Publication: English
Unique Identifier: 98348889

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MeSH Heading (Major): Amino Acids, Sulfur|*PH; Immunity|*; Nutrition|*; Polyamines|*
MeSH Heading: Animal; Dietary Proteins|AD; Human; Infection; Wounds and Injuries

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0899-9007
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amino Acids, Sulfur); 0 (Dietary Proteins); 0 (Polyamines)

Record 77 from database: MEDLINE
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Title: In vitro studies indicating antioxidative properties of rebamipide.
Author: Iinuma S; Naito Y; Yoshikawa T; Takahashi S; Takemura T; Yoshida N; Kondo M
Address: Department of Medicine, Otowa Hospital, Kyoto, Japan.
Source: Dig Dis Sci, 1998 Sep, 43:9 Suppl, 35S-39S
Abstract: Rebamipide is the first anti-gastric ulcer and antigastritis drug that not only increases endogenous prostaglandin in gastric mucosa but also scavenges oxygen-derived free radicals and inhibits their production. In the present paper, we have reviewed the antioxidative and antiinflammatory properties of rebamipide mainly demonstrated by in vitro studies. The study, using the electron paramagnetic resonance (EPR) spin trapping technique, showed that superoxide production was inhibited by rebamipide when isolated human neutrophils were stimulated with opsonized zymosan or Helicobacter pylori water extract in a dose-dependent manner. Chemiluminescence generated from neutrophils activated by H. pylori or formyl-methionyl-leucyl-phenylalanine was also decreased by the treatment with rebamipide. Rebamipide, at concentrations of 10(-5) and 10(-6) M, reduced the adherence of neutrophils to endothelial cells as well as the CD18 expression on neutrophils induced by H. pylori water extract. The EPR study also demonstrated the direct hydroxyl radical scavenging activity of rebamipide, and a kinetic study showed that the second-order rate constant for the reaction between rebamipide and hydroxyl radical was 2.24 x 10(10) M(-1)/s(-1). The inhibitory effect of rebamipide on lipid peroxidation induced by a free radical initiator was also demonstrated by the in vitro system using rat gastric mucosal homogenates. These data indicate that rebamipide offers a potential for protection against reactive oxygen- and activated neutrophil-associated gastric mucosal injury by scavenging hydroxyl radical and inhibiting neutrophil activation or lipid peroxidation.
Language of Publication: English
Unique Identifier: 98424146

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MeSH Heading (Major): Alanine|*AA/PD; Antioxidants|*PD; Gastric Mucosa|*DE; Quinolones|*PD; Reactive Oxygen Species|*ME
MeSH Heading: Animal; Anti-Ulcer Agents|PD; Human; In Vitro; Lipid Peroxidation|DE; Neutrophils|DE

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0163-2116
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Anti-Ulcer Agents); 0 (Antioxidants); 0 (Quinolones); 0 (Reactive Oxygen Species); 111911-87-6 (rebamipide); 6898-94-8 (Alanine)

Record 78 from database: MEDLINE
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Title: New perspectives and hope for cure-reflecting recent genetic developments in cystic fibrosis.
Author: Midro AT; Kulczycki LL
Address: Department of Clinical Genetics, Medical Academy, Bia…ystok, Poland.
Source: Mater Med Pol, 1992 Oct-Dec, 24:4, 253-5
Abstract: The isolation of cystic fibrosis gene at the CF locus assigned to the long arm of chromosome 7 band q31 and definition of its protein product named CFTR (cystic fibrosis transmembrane conductance regulator) permits to understand the basic defect in this inherited disorder known as cystic fibrosis (CF) or mucoviscidosis. A variety of mutations of CF gene was revealed and the most common, a deletion of the 3 nucleotides that encode phenylalanine (Delta F508) with the variable incidence among the different ethnic groups of CF patients was delineated. CF is a variable disease and genetic testing can be useful to explain this variation but to date the phenotype-genotype correlation is not clarified. Polymerase chain reaction (PCR) amplification is used to test CF gene in CF patients and their families but is not sufficiently genetically informative to population screening for carrier detections. Recently identified glycoprotein encoded by CF gene is responsible for the regulation of the membrane chloride channel of epithelial cells and the experiments used retro-virus-mediated gene transfer demonstrated complementation CF defect in vitro. The way for gene therapy in this disease is open. An alternative approach to use the germ line cells to CF gene therapy is prerequisite of the development of the preimplantation preconception genetic CF diagnosis. The researchers managed already to express human CFTR gene in vivo in cotton rats lungs through the viral delivery system. It will be generalized into the airways of CF patients with hope that normal CFTR will reverse the physiological defect in CF cells.
Language of Publication: English
Unique Identifier: 93360577

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MeSH Heading (Major): Cystic Fibrosis|*GE/*TH; Gene Therapy|*TD
MeSH Heading: Human; Infant, Newborn

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0025-5246
Country of Publication: POLAND

Record 79 from database: MEDLINE
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Title: Illegitimate transcription: its use in the study of inherited disease.
Author: Kaplan JC; Kahn A; Chelly J
Address: INSERM U129, Institut Cochin de Génétique Moléculaire, Paris, France.
Source: Hum Mutat, 1992, 1:5, 357-60
Abstract: In 1988, by using the powerful and accurate cDNA/PCR technique, it was demonstrated that there are very low levels of dystrophin mRNA in a variety of non-muscle tissues, including cultured fibroblasts and lymphoblastoid cell lines. The phenomenon was also shown for a number of other tissue-specific genes, including beta-globin, factors VIIIc and IX, anti-Müllerian hormone, L-pyruvate kinase, retinal blue pigment, phenylalanine hydroxylase. The level of transcript in inappropriate cells is exceedingly low, perhaps one mRNA per 100-1000 cells. This low-level ubiquitous transcription of tissue-specific genes was called "illegitimate" or "ectopic" transcription, and has been proven to occur for 17 gene transcripts to date. The mechanism and biological significance of illegitimate transcription are still obscure, but, since illegitimate transcripts exhibit the same pathology as legitimate transcripts, they have been useful tool in the study of already 9 inherited diseases. This strategy will be applied widely for diseases where samples from the appropriate tissue for study is difficult to obtain, or where an mRNA is easier or more informative to study than a genomic DNA (as for large genes, or where alternative splicing is involved).
Language of Publication: English
Unique Identifier: 93250832

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MeSH Heading (Major): Hereditary Diseases|*GE; Transcription, Genetic|*
MeSH Heading: Animal; DNA|GE; Human; Mutation; Polymerase Chain Reaction; RNA, Messenger|GE/ME; Tissue Distribution

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1059-7794
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (RNA, Messenger); 9007-49-2 (DNA)

Record 80 from database: MEDLINE
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Title: Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.
Author: Eisensmith RC; Woo SL
Address: Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030.
Source: Hum Mutat, 1992, 1:1, 13-23
Abstract: Mutations in the human phenylalanine hydroxylase gene producing phenylketonuria or hyperphenylalaninemia have now been identified in many patients from various ethnic groups. These mutations all exhibit a high degree of association with specific restriction fragment-length polymorphism haplotypes at the PAH locus. About 50 of these mutations are single-base substitutions, including six nonsense mutations and eight splicing mutations, with the remainder being missense mutations. One splicing mutation results in a 3 amino acid in-frame insertion. Two or 3 large deletions, 2 single codon deletions, and 2 single base deletions have been found. Twelve of the missense mutations apparently result from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides. Recurrent mutation has been observed at several of these sites, producing associations with different haplotypes in different populations. About half of all missense mutations have been examined by in vitro expression analysis, and a significant correlation has been observed between residual PAH activity and disease phenotype. Since continuing advances in molecular methodologies have dramatically accelerated the rate in which new mutations are being identified and characterized, this register of mutations will be updated periodically.
Language of Publication: English
Unique Identifier: 93244826

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|EN/*GE; Mutation|*; Phenylalanine|*ME; Phenylalanine Hydroxylase|*GE; Phenylketonuria|EN/*GE; Polymorphism (Genetics)|*
MeSH Heading: Amino Acid Sequence; Base Sequence; Codon|GE; Human; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1059-7794
Country of Publication: UNITED STATES
CAS Registry/EC Number: EC 1.14.16.1 (Phenylalanine Hydroxylase); 0 (Codon); 3617-44-5 (Phenylalanine)

Record 81 from database: MEDLINE
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Title: Artificial cells with emphasis on bioencapsulation in biotechnology.
Author: Chang TM
Address: Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
Source: Biotechnol Annu Rev, 1995, 1:, 267-95
Abstract: The most common use of artificial cells is for bioencapsulation of biologically active materials. Each artificial cell can contain combinations of materials. The permeability, composition and shape of an artificial cell membrane can be varied using different types of synthetic or biological materials. These possible variations in contents and membranes allow for large variations in the properties and functions of artificial cells. Artificial cells containing adsorbents have been a routine form of treatment in hemoperfusion for patients. This includes acute poisoning, high blood aluminum and iron, and supplement to dialysis in kidney failure. Artificial red blood cell substitutes based on modified hemoglobin are already in Phase I and Phase II clinical trials in patients. Artificial cell encapsulated cell cultures are being studied for the treatment of diabetes, liver failure, gene therapy and other conditions. Research on artificial cells containing enzymes includes their use for treatment in hereditary enzyme deficiency diseases and other diseases. Recent demonstration of extensive enterorecirculation of amino acids in the intestine has allowed oral administration to deplete specific amino acids. One example is phenylketonuria, an inborn error or metabolism resulting in high systemic phenylalanine levels. Preliminary clinical studies in patients using bioencapsulation of cells or enzymes have started. Artificial cells containing complex enzyme systems convert wastes like urea and ammonia into essential amino acids. Artificial cells are being used for the production of monoclonal antibodies, interferon and other biotechnological products. Other areas of biotechnological uses include drug delivery, and other areas of biotechnology, chemical engineering and medicine.
Language of Publication: English
Unique Identifier: 98369714

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MeSH Heading (Major): Genetic Engineering|*MT; Hemoperfusion|*MT
MeSH Heading: Aluminum|BL/IP/PO; Biotechnology|MT; Capsules; Cells; Clinical Trials, Phase I; Clinical Trials, Phase II; Diabetes Mellitus|TH; Drug Carriers; Drug Design; Gene Therapy|MT; Human; Iron|BL/IP/PO; Liver Failure|TH; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
Country of Publication: NETHERLANDS
CAS Registry/EC Number: 0 (Capsules); 0 (Drug Carriers); 7429-90-5 (Aluminum); 7439-89-6 (Iron)

Record 82 from database: MEDLINE
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Title: Present status of boron neutron capture therapy.
Author: Carlsson J; Sjöberg S; Larsson BS
Address: Department of Radiation Sciences, Uppsala University, Sweden.
Source: Acta Oncol, 1992, 31:8, 803-13
Abstract: The neutron capture reaction 10B(1n,4He)7Li produces two energetic particles, 4He2+ and 7Li3+ that are strongly cell toxic. Due to the short range of these nuclear fragments (5-9 microns) mainly those cells that have bound or internalized a 10B-containing substance are growth-inactivated. The most critical and difficult step in an efficient boron neutron capture therapy (BNCT) is the tumour targeting. It is today possible to synthesize a large number of boron compounds and conjugate them to tumour-seeking macromolecules, such as monoclonal antibodies or different polypeptides. The boron-containing substances presently considered for therapy are sulfhydryl boron hydride (BSH) and boron-phenylalanine, (BPA) for the treatment of gliomas and malignant melanomas respectively. Other boronated compounds considered are ligands for receptor-amplified tumour cells, antibodies for tumour cells with specific antigens and thioureas for treatment of melanotic melanomas. The required boron concentration is given by the relative dose due to neutron capture in 10B and that of the competing capture reactions in nitrogen and hydrogen. Capture in nitrogen produces protons with a range of about 10-11 microns and this gives a radiation dose to all cells in the neutron activated area. Calculations show that the local concentration of 10B near the critical radiation target, DNA, must be higher than 10 ppm (10 micrograms/g). Increased emphasis will be put on the development of combinations of treatments that fulfil the requirements for attacking the microscopic spread of the tumour.
Language of Publication: English
Unique Identifier: 93176437

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MeSH Heading (Major): Boron|*TU; Neoplasms|*RT; Neutron Capture Therapy|*MT
MeSH Heading: Clinical Trials; Human; Isotopes; Radiotherapy Dosage; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW LITERATURE
ISSN: 0284-186X
Country of Publication: NORWAY
CAS Registry/EC Number: 0 (Isotopes); 7440-42-8 (Boron)

Record 83 from database: MEDLINE
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Title: Intestinal mucosal amino acid catabolism.
Author: Wu G
Address: Departments of Animal Science, Medical Physiology, and Veterinary Anatomy and Public Health, and Faculty of Nutrition, Texas A&M University, College Station, TX 77843, USA.
Source: J Nutr, 1998 Aug, 128:8, 1249-52
Abstract: The small intestine is not only responsible for terminal digestion and absorption of nutrients, but it also plays an important role in catabolism of arterial glutamine and dietary amino acids. Most of glutamine and almost all of glutamate and aspartate in the diet are catabolized by small intestinal mucosa, and CO2 accounts for 56-64% of their metabolized carbons. The small intestinal mucosa also plays an important role in degrading arginine, proline and branched-chain amino acids, and perhaps methionine, lysine, phenylalanine, threonine, glycine and serine in the diet, such that 30-50% of these dietary amino acids are not available to extraintestinal tissues. Dietary amino acids are major fuels for the small intestinal mucosa and are essential precursors for intestinal synthesis of glutathione, nitric oxide, polyamines, purine and pyrimidine nucleotides, and amino acids (alanine, citrulline and proline), and are obligatory for maintaining intestinal mucosal mass and integrity. Because intestinal amino acid catabolism plays an important role in modulating dietary amino acid availability to extraintestinal tissues, it has important implications for the utilization efficiency of dietary protein and amino acids in animals and humans.
Language of Publication: English
Unique Identifier: 98353547

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MeSH Heading (Major): Amino Acids|BI/*ME; Intestinal Mucosa|*ME
MeSH Heading: Animal; Dietary Proteins|ME; Human; Intestine, Small|ME; Support, U.S. Gov't, Non-P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0022-3166
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amino Acids); 0 (Dietary Proteins)

Record 84 from database: MEDLINE
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Title: The clinical importance of hypochlorhydria (a consequence of chronic Helicobacter infection): its possible etiological role in mineral and amino acid malabsorption, depression, and other syndromes.
Author: Cater RE 2d
Address
Source: Med Hypotheses, 1992 Dec, 39:4, 375-83
Abstract: In a previous paper evidence was presented to show that Helicobacter-induced chronic gastritis is the probable cause of most chronic hypochlorhydria. In this article evidence is presented for the clinical relevance of reduced stomach acid secretion. Reduced mineral absorption is fairly well documented and has sound theoretical support from basic chemistry. Impaired digestion of protein has been suggested by a few studies. Small intestinal bacterial overgrowth in hypochlorhydria probably leads to putrefactive breakdown of the metobolically useful products of protein digestion, thereby reducing their availability for certain essential pathways. The possible lowering of tryptophan, tyrosine, and phenylalanine in the blood may be a precipitating factor in depression in hypochlorhydric patients. In reduced or absent stomach acid secretion a constellation of gastrointestinal symptoms has been consistently observed and reported by clinicians in the past, and treatment of the hypochlorhydria with hydrochloric acid or its substitutes has often been observed to be effective in reducing these symptoms.
Language of Publication: English
Unique Identifier: 93156643

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MeSH Heading (Major): Achlorhydria|*CO/*MI; Amino Acids|*ME; Depression|*ET/MI; Helicobacter Infections|*CO; Malabsorption Syndromes|*ET/MI; Minerals|*ME
MeSH Heading: Chronic Disease; Dietary Proteins; Digestion; Human; Syndrome

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0306-9877
Country of Publication: ENGLAND
CAS Registry/EC Number: 0 (Amino Acids); 0 (Dietary Proteins); 0 (Minerals)

Record 85 from database: MEDLINE
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Title: Entero-insular axis and diabetes mellitus.
Author: Creutzfeldt W
Address: Department of Medicine, University of Göttingen, Germany.
Source: Horm Metab Res Suppl, 1992, 26:, 13-8
Abstract: 1. The incretin effect (i.e. the difference between the insulin response after oral and i.v. glucose) is reduced in type 2 diabetes although GIP secretion is normal or exaggerated. This suggests an insensitivity of the diabetic B-cell to GIP. However, it could also indicate the lack of another not yet defined "incretin". 2. While CCK is a potent incretin in rats and dogs, physiological concentrations of this hormone do not stimulate insulin secretion in man in presence of elevated blood levels of glucose or phenylalanine in the physiological range. It also does not interact with GIP. 3. Glucagon-like peptide I (7-36) is a potent glucose-dependent stimulator of insulin secretion in animals and man. Preliminary data suggest release after oral glucose despite localization of the GLPI containing cells predominantly in the ileum and colon. More data are needed before GLPI (7-36) can be regarded as a physiological incretin and its role in type 2 diabetes assessed.
Language of Publication: English
Unique Identifier: 93146504

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MeSH Heading (Major): Diabetes Mellitus, Non-Insulin-Dependent|ET/*PP; Intestines|*PP; Islets of Langerhans|*PP/SE
MeSH Heading: Animal; Cholecystokinin|PH; Gastric Inhibitory Polypeptide|SE; Human; Insulin|SE; Peptide Fragments|PH

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0018-5043
Country of Publication: GERMANY
CAS Registry/EC Number: 0 (Peptide Fragments); 107444-51-9 (glucagon-like peptide I (7-36)); 11061-68-0 (Insulin); 59392-49-3 (Gastric Inhibitory Polypeptide); 9011-97-6 (Cholecystokinin)

Record 86 from database: MEDLINE
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Title: Mechanisms by which cancer chemotherapeutic drugs induce emesis.
Author: Cubeddu LX
Address: Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas.
Source: Semin Oncol, 1992 Dec, 19:6 Suppl 15, 2-13
Abstract: Because the area postrema seems essential for chemotherapy-induced vomiting, both circulating and/or neurally mediated stimuli in this area could trigger the emetic response. In our laboratories results of cross-circulation and direct intracerebroventricular infusion experiments in dogs do not support a role for circulating substances. The large increases in serum vasopressin induced by cisplatin were not blocked by inhibitors of the angiotensin-converting enzyme. In the ferret inhibition of serotonin synthesis with p-chloro-phenylalanine, administration of selective antagonists of 5-hydroxy-tryptamine3 (5-HT3) receptors, or visceral deafferentation inhibited the emetic response evoked by cisplatin or high-dose cyclophosphamide. The results suggest that serotonin plays an important role and that peripheral neural mechanisms are involved in the emetic response. The strong antiemetic efficacy of selective 5-HT3 antagonists also has been confirmed in humans. In cancer patients high-dose cisplatin increased the plasma and urinary levels of 5-hydroxy-indoleacetic acid (5-HIAA), but did not affect platelet and free plasma serotonin. The changes in 5-HIAA levels paralleled the onset and development of vomiting. No evidence of serotonin depletion has been obtained after high-dose cisplatin. Dacarbazine, another strongly emetogenic agent, increased urinary 5-HIAA; however, only small increases in 5-HIAA were produced with low-dose cisplatin or cyclophosphamide-containing regimens. Thus, emetogenicity appears to be directly related to the ability of the cytotoxic agent to release serotonin. In humans, antiemetics such as ondansetron, metoclopramide, and dexamethasone did not effect high-dose cisplatin-induced increases in serotonin metabolism. Therefore, these antiemetics seem not to affect the amount of serotonin released. The mechanism by which chemotherapeutic drugs induce serotonin release is unknown; however, release may occur by direct cytotoxicity on the gastrointestinal mucosa, including the enterochromaffin cells. Delayed emesis appears to be mediated by 5-HT3-independent mechanisms. It is proposed that emesis that develops despite high-dose ondansetron (residual emesis) should be considered delayed emesis. Residual and delayed episodes of emesis have similar time courses, are characterized by very mild emetic episodes and poor response to 5-HT3 antagonists, and are not associated with increases in serotonin metabolism.
Language of Publication: English
Unique Identifier: 93134400

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MeSH Heading (Major): Antineoplastic Agents|AE/*PD; Nausea|*CI/PC; Vomiting|*CI/PC
MeSH Heading: Animal; Chemoreceptors|DE; Human; Models, Biological; Ondansetron|TU; Serotonin|PH; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0093-7754
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Antineoplastic Agents); 50-67-9 (Serotonin); 99614-02-5 (Ondansetron)

Record 87 from database: MEDLINE
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Title: Therapeutic uses of microencapsulated genetically engineered cells.
Author: Chang TM; Prakash S
Address: Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, QC, Canada.
Source: Mol Med Today, 1998 May, 4:5, 221-7
Abstract: Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.
Language of Publication: English
Unique Identifier: 98275749

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MeSH Heading (Major): Cell Transplantation|*; Gene Therapy|*MT; Genetic Engineering|*
MeSH Heading: Animal; Biotechnology; Capsules; Human; Kidney Failure|TH; Rats; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1357-4310
Country of Publication: ENGLAND
CAS Registry/EC Number: 0 (Capsules)

Record 88 from database: MEDLINE
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Title: A review of recent advances in understanding ochratoxicosis.
Author: Marquardt RR; Frohlich AA
Address: Department of Animal Science, University of Manitoba, Winnipeg, Canada.
Source: J Anim Sci, 1992 Dec, 70:12, 3968-88
Abstract: Ochratoxin A (OA) is a toxin that contains an isocoumarin moiety linked by a peptide bond to phenylalanine. It is produced by certain Penicillium (mainly P. verrucosum) and Aspergillus (mainly A. alutaceus) species of storage fungi. Total amounts of OA and other related toxins produced by these fungi are influenced by many factors. Several forms of OA have been discovered, some of which are highly toxic, whereas others have lower toxicity. Ochratoxin A has been detected in foods, feeds, animal tissues, and human blood in both Europe and North America. It has been implicated in the fatal human disease Balkan endemic nephropathy, has been shown to be a powerful carcinogen in rodents, and produces many other adverse effects in animals. It is absorbed passively throughout the gastrointestinal tract and in an active manner in the kidney. It is subjected to intestinal secretion and reabsorption via enterohepatic recycling. Binding of OA in the blood to the albumin fraction and recycling in the bile and kidney contributes to its long half-life in animals. Ochratoxin A is hydrolyzed to its nontoxic alpha form (O alpha) by microorganisms in the rumen, cecum, and large intestine. The toxin is excreted primarily in the urine as O alpha and to a lesser degree as OA; smaller amounts of OA and O alpha are generally excreted in the feces. Three distinct mechanisms of OA toxicity have been proposed; other toxic effects of OA seem to be secondary in nature. Several different strategies can be employed for controlling or neutralizing the effect of OA, including the use of proper storage conditions, the use of specific adsorbents to reduce absorption of OA, and the feeding OA-contaminated feedstuffs to ruminants. Antioxidants such as ascorbic acid have been shown to reduce the toxic effects of OA in laying hens. In summary, OA contamination of cereal food and feed may occur, given appropriate conditions. Implementation of suitable procedures may eliminate or minimize this potentially serious problem.
Language of Publication: English
Unique Identifier: 93115110

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MeSH Heading (Major): Animals, Domestic|*; Animals, Laboratory|*; Food Microbiology|*; Ochratoxins|PK/*PO
MeSH Heading: Animal; Human; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0021-8812
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Ochratoxins)

Record 89 from database: MEDLINE
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Title: Molecular biology of Alzheimer's amyloid--Dutch variant.
Author: Wisniewski T; Frangione B
Address: Department of Neurology, New York University Medical Center, NY 10016.
Source: Mol Neurobiol, 1992 Spring, 6:1, 75-86
Abstract: Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) (or familial cerebral amyloid angiopathy) and familial Alzheimer's disease (FAD) share several properties. Both are autosomal dominant forms of cerebral amyloidosis characterized by beta-amyloid (A beta) deposition. In HCHWA-D the A beta is predominantly found in blood vessels and in early parenchymal plaques, whereas in AD parenchymal A beta deposits in the form of senile plaques and neurofibrillary tangles are a more prominent finding. Point mutations in the amyloid precursor protein (APP) have recently been described, in both conditions. A G to C transversion at codon 618 (extracellular portion of APP695), producing a single amino acid substitution of glutamine instead of glutamine acid, occurs in HCHWA-D; whereas mutations at codon 642 in the intramembrane region of APP695 (phenylalanine, isoleucine, or glycine instead of valine) are associated with early onset FAD. This suggests that the site of particular mutations in the APP gene and the type of amino acid substitution in the APP holoprotein are more important in determining clinicopathological phenotype and age at which A beta is deposited. Thus FAD and HCHWA-D can be regarded as two sides of the same coin.
Language of Publication: English
Unique Identifier: 93098892

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MeSH Heading (Major): Alzheimer's Disease|GE/*ME; Amyloid|GE/*ME; Amyloid beta-Protein Precursor|*GE; Cerebral Amyloid Angiopathy|GE/*ME
MeSH Heading: Amyloid beta-Protein|BI; Codon; Exons; Genes, Dominant; Human; Middle Age; Mutation; Netherlands; Neurofibrillary Tangles|CH; RNA Processing, Post-Transcriptional

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0893-7648
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amyloid beta-Protein Precursor); 0 (Amyloid beta-Protein); 0 (Amyloid); 0 (Codon)

Record 90 from database: MEDLINE
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Title: Pharmacotherapy of attention-deficit/hyperactivity disorder in adults.
Author: Wender PH
Address: Department of Psychiatry, University of Utah School of Medicine, Salt Lake City 84132, USA.
Source: J Clin Psychiatry, 1998, 59 Suppl 7:, 76-9
Abstract: A history of childhood attention-deficit/hyperactivity disorder (ADHD) is a mandatory prerequisite for the diagnosis of adult type ADHD, for which no DSM criteria exists. Since the diagnosis must be made retroactively, tentative criteria have been designed to establish the presence of the childhood disorder. In the 1970s, I advanced the hypothesis that "minimal brain dysfunction" (as ADHD was called) might be produced by decreased catecholaminergic function. A total of over 300 ADHD patients have been included in treatment studies, including 224 patients who received stimulants in four double-blind, placebo-controlled trials: three of methylphenidate (N = 176) and one of pemoline (N = 48). An additional 79 patients have been included in open-label trials of pargyline, selegiline, bupropion, levodopa, phenylalanine, and tyrosine. Altogether, these studies have demonstrated the efficacy of methylphenidate, pemoline, and monoamine oxidase-B (MAO-B) inhibitors when administered to adult ADHD patients; a robust response was produced in 60% of the patients. Bupropion and selegiline were effective in the open-label studies and should be systematically evaluated. A long-term study is being conducted with methylphenidate maintenance; patients have been followed for as long as 5 years, and little, if any, drug tolerance has been observed. Treatment of adult patients who have ADHD is symptomatic, not curative, but the combination of medication and psychotherapy may offer life-changing opportunities to individuals who suffer from the disorder.
Language of Publication: English
Unique Identifier: 98343650

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MeSH Heading (Major): Attention Deficit Disorder with Hyperactivity|DI/*DT
MeSH Heading: Adult; Age Factors; Central Nervous System Stimulants|TU; Clinical Trials; Combined Modality Therapy; Double-Blind Method; Follow-Up Studies; Human; Methylphenidate|TU; Monoamine Oxidase|TU; Pemoline|TU; Placebos; Psychotherapy; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0160-6689
Country of Publication: UNITED STATES

Record 91 from database: MEDLINE
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Title: Treatment of osteoarthritis with aspartame.
Author: Edmundson AB; Manion CV
Address: Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
Source: Clin Pharmacol Ther, 1998 May, 63:5, 580-93
Abstract: OBJECTIVE: The binding of sweet-tasting compounds in a human (Mcg) Bence-Jones dimer has been characterized by x-ray crystallography. Aspartame binding in this immunoglobulin fragment is remarkable. Unexpected pain relief noted by A.B.E., a crystallographer with diagnosed osteoarthritis, suggested that the accommodation of aspartame in the active site of the dimer may represent surrogate binding by other proteins, with analgesia as the outcome. METHODS: X-ray analysis of the complex of aspartame and the Bence-Jones dimer was conducted with crystalline Mcg protein and pure aspartame. A single-blind (n = 1) study to confirm analgesia was completed by administration of aspartame to A.B.E. A controlled double-blind trial was performed in patients with x-ray-documented osteoarthritis. Pain and performance changes were evaluated with use of two doses of placebo and two doses of aspartame. Effects on bleeding time were then evaluated by determination of template bleeding times in 34 normal volunteers. Finally, antipyretic effects were studied in Sprague-Dawley rats given intramuscular turpentine injections. RESULTS: Aspartame binding in the Bence-Jones dimer was verified by x-ray crystallography. Improvements in performance and pain relief were observed in A.B.E. at p < 0.001. Decreased pain and improved performance were also observed in patients with osteoarthritis (p < 0.001). Mild antihemostatic responses were observed in bleeding times after aspartame treatment. Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile responses in the treated rats (p < 0.01). CONCLUSIONS: L-Aspartyl-L-phenylalanine methyl ester is biologically active and appears to relieve pain, induce mild antithrombotic effects in humans, and decrease fever in animals.
Language of Publication: English
Unique Identifier: 98294287

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MeSH Heading (Major): Aspartame|CH/*ME/*TU; Osteoarthritis|*DT
MeSH Heading: Animal; Bence Jones Protein|ME; Crystallography, X-Ray; Fever|DT; Human; Molecular Structure; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0009-9236
Country of Publication: UNITED STATES

Record 92 from database: MEDLINE
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Title: Signal transduction in cells following binding of chemoattractants to membrane receptors.
Author: Dillon SB; Verghese MW; Snyderman R
Address: Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Source: Virchows Arch B Cell Pathol Incl Mol Pathol, 1988, 55:2, 65-80
Abstract: Binding of chemoattractants to specific cell surface receptors on human polymorphonuclear leukocytes (PMNs) initiates a variety of biologic responses, including directed migration (chemotaxis), release of superoxide anions, and lysosomal enzyme secretion. Chemoattractant receptors belong to a large class of receptors which utilize the hydrolysis of polyphosphoinositides to initiate Ca2+ mobilization and cellular activation. Receptor occupancy leads to phospholipase C-mediated hydrolysis of polyphosphoinositol 4,5-bisphosphate (PIP2) yielding inositol 1,4,5-trisphosphate (IP3) and 1,2 sn-diacylglycerol (DAG). These products synergize to initiate cell activation via calcium mobilization (IP3) and protein kinase C activation (DAG). Pertussis toxin, which ADP-ribosylates and inactivates some GTP binding proteins (G proteins), abolishes all chemoattractant-induced responses, including Ca2+ mobilization, IP3 and DAG production, enzyme secretion, superoxide production and chemotaxis. Direct evidence for chemoattractant receptor: G protein coupling was obtained using PMN membrane preparations which contain a Ca2+-sensitive phospholipase C. Hydrolysis of polyphosphoinositides at resting intracellular Ca2+ levels (100 nm) was only observed when the membranes were stimulated with the chemoattractant N-formyl-methyl-leucyl-phenylalanine (fMet-Leu-Phe) in the presence of GTP. Myeloid cells contain two distinct pertussis toxin substrates of similar molecular weight (40 and 41 kD). The 41 kD substrate resembles Gi, whereas a 40 kD substrate is physically associated with a partially purified fMet-Leu-Phe receptor preparation and may therefore represent a novel G protein involved in chemoattractant-stimulated responses. Metabolism of 1,4,5-IP3 to inositol proceeds via two distinct pathways in PMNs: (1) degradation to 1,4-IP2 and 4-IP1 or (2) conversion to 1,3,4,5-IP4, 1,3,4-IP3, 3,4-IP2 and 3-IP1. Initial formation (0-30 s) of 1,4,5-IP3 and DAG occurs at ambient intracellular Ca2+ levels, whereas formation of 1,3,4-IP3 and a second sustained phase of DAG production (30 s-10 min) require elevated cytosolic Ca2+ influx. The later peak of DAG, which is not derived from phosphoinositides, appears to be required for stimulation of respiratory burst activity. Products formed during activation can feed back to attenuate chemoattractant receptor-mediated stimulation of phospholipase C by uncoupling receptor-G protein-phospholipase C interaction.
Language of Publication: English
Unique Identifier: 88322838

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MeSH Heading (Major): Chemotactic Factors|*ME; Neutrophils|DE/*ME
MeSH Heading: Cell Movement|DE; Cytotoxins|PD; G-Proteins|ME; Human; Models, Biological; N-Formylmethionine Leucyl-Phenylalanine|PD; Phagocytosis|DE; Phospholipase C|ME; Protein Kinase C|PH; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0340-6075
Country of Publication: GERMANY
CAS Registry/EC Number: EC 2.7.1.- (Protein Kinase C); EC 3.1.4.3 (Phospholipase C); 0 (Chemotactic Factors); 0 (Cytotoxins); 0 (G-Proteins); 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)

Record 93 from database: MEDLINE
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Title: Antioxidant potential of ferulic acid.
Author: Graf E
Address: Technology Center, Tastemaker, Cincinnati, OH 45216.
Source: Free Radic Biol Med, 1992 Oct, 13:4, 435-48
Abstract: Ferulic acid is a ubiquitous plant constituent that arises from the metabolism of phenylalanine and tyrosine. It occurs primarily in seeds and leaves both in its free form and covalently linked to lignin and other biopolymers. Due to its phenolic nucleus and an extended side chain conjugation, it readily forms a resonance stabilized phenoxy radical which accounts for its potent antioxidant potential. UV absorption by ferulic acid catalyzes stable phenoxy radical formation and thereby potentiates its ability to terminate free radical chain reactions. By virtue of effectively scavenging deleterious radicals and suppressing radiation-induced oxidative reactions, ferulic acid may serve an important antioxidant function in preserving physiological integrity of cells exposed to both air and impinging UV radiation. Similar photoprotection is afforded to skin by ferulic acid dissolved in cosmetic lotions. Its addition to foods inhibits lipid peroxidation and subsequent oxidative spoilage. By the same mechanism ferulic acid may protect against various inflammatory diseases. A number of other industrial applications are based on the antioxidant potential of ferulic acid.
Language of Publication: English
Unique Identifier: 93013131

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MeSH Heading (Major): Antioxidants|*; Coumaric Acids|*/AN/CH/ME/PD/TU
MeSH Heading: Animal; Free Radical Scavengers; Human; Plants|CH

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0891-5849
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Antioxidants); 0 (Coumaric Acids); 0 (Free Radical Scavengers); 1135-24-6 (ferulic acid)

Record 94 from database: MEDLINE
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Title: Copper, lysyl oxidase, and extracellular matrix protein cross-linking.
Author: Rucker RB; Kosonen T; Clegg MS; Mitchell AE; Rucker BR; Uriu Hare JY; Keen CL
Address: Department of Nutrition, University of California, Davis 95616, USA. rbrucker@ucdavis.edu
Source: Am J Clin Nutr, 1998 May, 67:5 Suppl, 996S-1002S
Abstract: Protein-lysine 6-oxidase (lysyl oxidase) is a cuproenzyme that is essential for stabilization of extracellular matrixes, specifically the enzymatic cross-linking of collagen and elastin. A hypothesis is proposed that links dietary copper levels to dynamic and proportional changes in lysyl oxidase activity in connective tissue. Although nutritional copper status does not influence the accumulation of lysyl oxidase as protein or lysyl oxidase steady state messenger RNA concentrations, the direct influence of dietary copper on the functional activity of lysyl oxidase is clear. The hypothesis is based on the possibility that copper efflux and lysyl oxidase secretion from cells may share a common pathway. The change in functional activity is most likely the result of posttranslational processing of lysyl oxidase. Copper is essential for organic cofactor formation in amine oxidases such as lysyl oxidase. Copper-containing amine oxidases have peptidyl 2,4,5 tri(oxo)phenylalanine (TOPA) at their active centers. TOPA is formed by copper-catalyzed oxidation of tyrosine, which takes place as part of Golgi or trans-Golgi processing. For lysyl oxidase, recent evidence (Science 1996;273:1078-84) indicates that as an additional step, a lysyl group at the active center of lysyl oxidase reacts with TOPA or its precursor to form lysyl tyrosylquinone.
Language of Publication: English
Unique Identifier: 98246569

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MeSH Heading (Major): Copper|*ME; Extracellular Matrix Proteins|CH/*ME; Protein-Lysine 6-Oxidase|BI/CH/*ME
MeSH Heading: Animal; Golgi Apparatus|ME; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0002-9165
Country of Publication: UNITED STATES

Record 95 from database: MEDLINE
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Title: Strategies for correcting the delta F508 CFTR protein-folding defect.
Author: Brown CR; Hong Brown LQ; Welch WJ
Address: Department of Medicine, The University of California, San Francisco 94143, USA.
Source: J Bioenerg Biomembr, 1997 Oct, 29:5, 491-502
Abstract: Many human diseases arise as a result of mutations within genes encoding essential proteins. In many cases, the mutations are not so severe as to render the protein biologically inactive. Rather, the mutations oftentimes result in only subtle protein-folding abnormalities. In the case of the CFTR protein, a mutation leading to the loss of a single amino acid is responsible for the diseased state in the majority of individuals with cystic fibrosis. Here the newly synthesized mutant CFTR protein, missing a phenylalanine residue at position 508 (delta F508 CFTR), is unable to transit from the endoplasmic reticulum to the plasma membrane, where it functions as a regulator of chloride transport. All of the available evidence indicate that the newly synthesized delta F508 CFTR protein adopts a slightly altered conformation and therefore is retained at the level of the endoplasmic reticulum, ostensibly by the actions of the cellular quality control system. Because the mutant protein is capable of functioning as a chloride channel, developing ways to elicit its release out of the ER and to the plasma membrane has important clinical implications. Herein, we discuss our recent studies showing that the protein-folding defect associated with the delta F508 CFTR mutation, as well as a number of other temperature-sensitive mutations, can be overcome by strategies designed to influence protein folding inside the cell. Specifically we show that a number of low-molecular-weight compounds, all of which are known to stabilize proteins in their native conformation, are effective in rescuing the folding and/or processing defects associated with different mutations that oftentimes lead to human disease.
Language of Publication: English
Unique Identifier: 98170884

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MeSH Heading (Major): Cystic Fibrosis|DT/GE/*TH; Cystic Fibrosis Transmembrane Conductance Regulator|*CH/DE/*GE; Mutation|*/DE; Protein Folding|*
MeSH Heading: Antibiotics, Aminoglycoside|TU; Gene Therapy; Human; Molecular Chaperones|TU; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0145-479X
Country of Publication: UNITED STATES

Record 96 from database: MEDLINE
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Title: A summary of mechanistic hypotheses of gabapentin pharmacology.
Author: Taylor CP; Gee NS; Su TZ; Kocsis JD; Welty DF; Brown JP; Dooley DJ; Boden P; Singh L
Address: Department of Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48105, USA.
Source: Epilepsy Res, 1998 Feb, 29:3, 233-49
Abstract: Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).
Language of Publication: English
Unique Identifier: 98211510

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MeSH Heading (Major): Acetic Acids|*PD/PK/*TU; GABA|*ME
MeSH Heading: Analgesics|PD/TU; Animal; Anti-Anxiety Agents|AD/TU; Anticonvulsants|PD/TU; Brain|DE/PH; Calcium Channels|CH/DE/PH; Human; Models, Neurological; Neuroprotective Agents|PD/TU; Neurotransmitters|PH; Pain; Sodium Channels|PH; Synapses|DE/PH; Tissue Distribution

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0920-1211
Country of Publication: NETHERLANDS

Record 97 from database: MEDLINE
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Title: Amino acids for the measurement of protein synthesis in vivo by PET.
Author: Vaalburg W; Coenen HH; Crouzel C; Elsinga PH; Långström B; Lemaire C; Meyer GJ
Address: Department of Nuclear Medicine, University Hospital, Groningen, The Netherlands.
Source: Int J Rad Appl Instrum [B], 1992 Feb, 19:2, 227-37
Abstract: In principle, PET in combination with amino acids labelled with positron-emitting radionuclides and kinetic metabolic models, can quantify local protein synthesis rates in tissue in vivo. These PET measurements have clinical potential in, for example, oncology, neurology and psychiatry. An optimal positron-emitting amino acid for the measurement of PSR has a high protein incorporation, can easily be prepared by automated equipment and has minimal non-protein radioactive metabolites. Presently L-[methyl-11C]methionine, L-[1-11C]leucine, L-[1-11C]tyrosine, L-[1-11C]phenylalanine, L-[1-11C]methionine and L-[2-18F]fluorotyrosine are under evaluation in normal volunteers and/or in patients. Several other amino acids are suggested. No comparison of the clinical usefulness of the different amino acids in man is yet available. Because of the longer half life of 18F compared to 11C, [18F]fluoro amino acids may have advantages over [11C]amino acids for the investigation of tissue with relative slow protein synthesis, such as brain, and for application in institutions with an off site, but nearby cyclotron. The half life of [13N]amino acids is considered to be too short for flexible clinical application. As yet no metabolic compartmental model has been investigated for [13N]amino acids. For routine application reliable preparation of the radiopharmaceutical is essential. Of all the amino acids under evaluation, a reliable, high yield, easy to automate production procedure is available for L-[methyl-11C]methionine only. It is however unlikely that this tracer can accurately measure PSR because of its non-protein metabolism. For the other amino acids the main problems in production are associated with complex multistep syntheses and/or low radiochemical yields, complex purification methods and the need to isolate the L-enantiomer. The kinetic metabolic models under investigation, consist of 4 or 5 compartments depending on the necessity to compensate for labelled metabolites. The metabolic profile of the amino acids is mainly extracted from animal experiments. Because of the number and amount of labelled metabolites in plasma, [11C]carboxylic labelled amino acids are preferred to amino acids with carbon-11 in another position. As yet no recommendation can be given on the optimal labelled amino acid(s) for PSR measurement in vivo nor on the methods to prepare the amino acids reported for this purpose.
Language of Publication: English
Unique Identifier: 92290832

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MeSH Heading (Major): Amino Acids|*ME; Proteins|*BI
MeSH Heading: Animal; Carbon Radioisotopes|DU; Fluorine Radioisotopes|DU; Human; Isotope Labeling|MT; Kinetics; Tomography, Emission-Computed

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0883-2897
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Amino Acids); 0 (Carbon Radioisotopes); 0 (Fluorine Radioisotopes); 0 (Proteins)

Record 98 from database: MEDLINE
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Title: Amino acid metabolism in pediatric patients.
Author: Imura K; Okada A
Address: Department of Pediatric Surgery, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan.
Source: Nutrition, 1998 Jan, 14:1, 143-8
Abstract: As with energy requirements, protein requirements are relatively much greater in infants and decline progressively with age. Amino acid metabolism in pediatric patients is characterized by the following differences. The requirement for essential amino acids in neonates is larger than that in adults. Because of low activity of phenylalanine hydroxylase and cystathionase, hyperphenylalaninemia and hypermethioninemia tend to occur, whereas tyrosine and cysteine tend to be deficient. In addition to cysteine and tyrosine, histidine, lysine, arginine and taurine are considered as semiessential amino acids. Nowadays there are different kinds of amino acid formulas to satisfy these specific requirements, and most of these formulas are intended to normalize the plasma aminogram. However, the nutritional benefit of these formulas for growth and development is still not completely proven, and the pharmacological use for specific diseases is expected with some modification of these formulas.
Language of Publication: English
Unique Identifier: 98100354

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MeSH Heading (Major): Amino Acids|*ME
MeSH Heading: Adult; Amino Acids, Essential|AD; Child; Child, Preschool; Dietary Proteins|AD; Human; Infant; Infant Food; Infant, Newborn; Nutritional Requirements; Proteins|ME; Surgical Procedures, Operative

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0899-9007
Country of Publication: UNITED STATES

Record 99 from database: MEDLINE
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Title: Scleroderma-like skin indurations in a child with phenylketonuria: a clinicopathologic correlation and review of the literature.
Author: Nova MP; Kaufman M; Halperin A
Address: Pacific Dermatopathology Laboratories, San Diego, CA 92110.
Source: J Am Acad Dermatol, 1992 Feb, 26:2 Pt 2, 329-33
Abstract: Scleroderma-like skin lesions are one sequela of phenylketonuria. We describe a child with phenylketonuria and associated dermal connective tissue changes consistent with early inflammatory scleroderma. The severity of the skin lesions apparently waned with dietary restriction of phenylalanine.
Language of Publication: English
Unique Identifier: 92235359

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MeSH Heading (Major): Phenylketonuria|*CO; Scleroderma, Circumscribed|*ET/PA
MeSH Heading: Biopsy; Case Report; Female; Human; Infant

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW OF REPORTED CASES
ISSN: 0190-9622
Country of Publication: UNITED STATES

Record 100 from database: MEDLINE
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Title: Protein turnover in the kidney and the whole body in humans.
Author: Garibotto G; Tessari P; Robaudo C; Zanetti M; Saffioti S; Vettore M; Inchiostro S; Sacco P; Deferrari G; Tizianello A
Address: Department of Internal Medicine, University of Genoa, Italy.
Source: Miner Electrolyte Metab, 1997, 23:3-6, 185-8
Abstract: For a better understanding of protein synthesis and degradation in the human kidney, the arteriovenous difference technique across the kidney, splanchnic organs, and leg muscle was combined with labeled leucine and phenylalanine isotope dilution models. Results indicate that in the postabsorptive state, the protein balance across the human kidney is negative because the rate of leucine release from protein degradation is greater than the amount used for protein synthesis. In the splanchnic bed, net protein balance is neutral since the amount of leucine deriving from protein degradation is similar to the amount utilized for protein synthesis. In the leg muscle, protein degradation exceeds protein synthesis. The kidney exhibits the highest leucine metabolic activity when expressed in terms of total organ leucine content. The estimated fractional protein synthesis rate in the human kidney is about 40% per day (vs. about 2% in muscle and 12% in the splanchnic bed). The human kidney presents high rates of protein turnover and accounts for a significant fraction of whole-body protein degradation, protein synthesis, and leucine oxidation.
Language of Publication: English
Unique Identifier: 98048354

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MeSH Heading (Major): Kidney|*ME; Muscle, Skeletal|*ME; Proteins|*ME; Viscera|*ME
MeSH Heading: Animal; Caproates|ME; Human; Leg; Leucine|ME; Phenylalanine|ME; Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0378-0392
Country of Publication: SWITZERLAND

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