Phenylalanine Hydroxylase and Tyrosine Aminotransferase in Human Fetal and Adult Liver

Delvalle, J A; Greengard, Olga

doi:10.1203/00006450-197711010-00002

Cited by 20 publications

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“…With respect to fetal tyrosine content, however, the discrepancy should be less pronounced. The human fetal liver, by about the tenth wk, attains at least 5Wo of its adult phenylalanine hydroxylase activity (13,45). Although the phenylketonuric mother is devoid of the enzyme, its heterozygous fetus (with at least 25% of the normal aduli phenylalanine hidroxylase activity) should be able to convert some of the excess circulating phenylalanine to raise its own tyrosine levels to even above normal.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

et al. 1982

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SummaryA new model has been developed for the study of maternal phenylketonuria. Beginning on the 12th day of gestation the diet of pregnant rats was supplemented with 0.5% a-methylphenylalanine and 3% phenylalanine. This resulted in an 83% reduction of hepatic phenylalanine hydroxylase activity. The maternal plasma phenylalanine ;vas elevated 10-20-fold for two-thirds of the day, but the degree and persistence of the fetal hyperphenylalaninemia may have been even greater. The brain phenylalanine concentrations in the fetus were raised up to 2900 nmole/g brain, whereas the highest level observed in the dam was 382 nmole/g. Experimentally-treated fetuses showed small reductions in both body and brain weight when compared to age-matched controls; however, no differences were seen in crown to rump length, litter size, DNA and protein concentrations per g, or in postnatal survival. Initiation of the diet at conception rather than on the 12th day caused a significantly greater inhibition of fetal growth, and 21% mortality.The fetal cerebral concentrations of metbionine and the branched chain amino acids (valine, leucine and isoleucine) were decreased by hyperphenylalaninemia. From the 16th day on, the concentration of the inhibitor neurotransmitter glycine was elevated. Cerebral serotonin showed a 20-30% deficit and its primary metabolite 5-hydroxyindoleacetic acid a 71-77% deficit.Of twelve enzymes quantified in the brains of hyperphenylalaninemic fetuses only phosphoserine phosphatase showed any change. From the 20th to the 22nd day of gestation its activity was 46-67% higher in experimental than in normal fetuses. Measurement on the 22nd day of gestation showed that the increases in phosphoserine phosphatase activity and glycine content were present in brain stem, cerebellum, and forebrain. SpeculationThis new animal model of maternal phenylketonuria is suitable for elucidating the mechanisms of abnormal development of heterozygous children of phenylketonuric mothers. ~6 r~h e n~l a l aninemia in the dam is responsible for gross elevations in fetal brain phenylalanine content and the bioch'kmical consequences of this elevation, such as pertubations in the levels of glycine, serotonin and branched chain amino acids, which may be responsible for the lasting damage to cerebral function.Several studies have indicated that mental retardation is associated not only with phenylketonuria but also with the majority of heterozygous infants of phenylketonuric mothers (8,16,17,30,38). This indicates that permanent damage of cerebral functions can occur if severe hyperphenylalaninemia is restricted to intrauterine life. The common end result. mental retardation. does not necessarily imply a common pathogenic pathway: the &mediate impact of the same metabolic abnormality may well be different at different stages of ontogeny. Studies of phenylketonurics and rats subjected to experimental hyperphenylalaninemia have provided some insights into the postnatal biochemical changes; however, little is known about those occurring in ute...

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Section: Discussionmentioning

confidence: 99%

The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

et al. 1982

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“…In the fetal liver, this pathway is suggested to be rate limited by tyrosine aminotransferase, an enzyme that converts tyrosine to 4-hydroxylphenylpyruvate (Ohisalo et al, 1982). Like GSTZ1/MAAI, tyrosine aminotransferase possesses very low activity in the fetus and increases rapidly after birth (Delvalle and Greengard, 1977;Andersson et al, 1980;Ohisalo et al, 1982). This suggests that maleylacetoacetate exists at a very low concentration in fetal liver, so that slow nonenzymatic conversion to fumarylacetoacetate could be sufficient for its degradation (Fernán-dez-Cañón et al, 2002).…”

Section: Et Almentioning

confidence: 99%

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Gu²,

James³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Glutathione transferase 1 (GSTZ1), also known as maleylacetoacetate isomerase, catalyzes the penultimate step of tyrosine catabolism and metabolizes several ␣-halocarboxylic acids, including dichloroacetic acid (DCA), an investigational drug used for lactic acidosis and, recently, solid tumors. Age-related differences have been suggested in DCA pharmacotoxicology, but no information is available on GSTZ1 ontogeny in humans. Here, we investigated the cytosolic GSTZ1 developmental expression pattern and the influence of haplotype on GSTZ1 activity with DCA by using human livers from donors between 10 weeks gestation and 74 years. GSTZ1 expression was very low in fetal livers (<2 pmol of GSTZ1/mg cytosol). The expression began to increase after birth in an age-dependent manner until age 7 years. GSTZ1 was then sustained at stable, yet variable, levels (median, 20.0 pmol/mg cytosol; range, 4.8-47.3 pmol/mg cytosol) until age 74 years. GSTZ1 activity with DCA was strongly associated with haplotype and expression level. Samples homozygous or heterozygous for GSTZ1A exhibited ϳ3-fold higher DCA dechlorinating activity than samples carrying other alleles at a given level of expression. The correlations (r 2 ) between activity and expression were 0.90 and 0.68, respectively, for GSTZ1A carriers (n ‫؍‬ 11) and noncarriers (n ‫؍‬ 61). GSTZ1 is expressed in mitochondria in addition to cytosol. The GSTZ1A allele exhibited similar effects in the mitochondrial fraction by conferring a higher activity with DCA. In summary, we report a neonatal onset and an age-related increase in GSTZ1 protein expression during human liver development. Haplotype influenced GSTZ1 activity with DCA but not protein expression.

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“…Thus, adding Tyr to the maternal diet may be inappropriate for the fetus. Phenylalanine hydroxylase and biopterin cofactor are present in the human fetal liver from the eleventh week of pregnancy (Delvalle and Greengard, 1977).…”

Section: Discussionmentioning

confidence: 99%

Outcome of pregnancy in the rat with mild hyperphenylalaninaemia and hypertyrosinaemia: Implications for the management of “human maternal PKU”

Lewis

Lyon

1984

J of Inher Metab Disea

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In attempting to determine the effects of mildly elevated maternal phenylalanine (Phe) blood levels on the developing fetal rat brain, a dietary supplement of Phe was given, under taste cover of Aspartame. Phe and tyrosine (Tyr) levels were mildly elevated throughout pregnancy without evidence of malnutrition. Mild hyperphenylalaninaemia with concurrent hypertyrosinaemia induced in rats prior to conception resulted in microcephaly and lasting behavioural problems in the offspring, specifically hyperactivity and learning difficulties. Dams fed Tyr to produce Tyr levels equivalent to the Phe-fed animals showed only the learning difficulties among the offspring. alpha-Methyl Phe, a Phe hydroxylase inhibitor, fed in conjunction with Phe, at the level relevant to these experiments, resulted in raised Tyr levels and does not provide a better method of determining whether mildly elevated maternal Phe levels alone, or Phe and Tyr in combination, cause the abnormality found in the offspring of Phe-supplemented dams. Therapeutic addition of Tyr to diets of mothers with even mild hyperphenylalaninaemia should be approached with caution as mild co-elevation of Phe and Tyr in the fetus may be harmful. In the face of such a possible therapeutic dilemma alternatives, such as dietary additions of other essential amino acids to limit fetal brain damage, need to be explored.

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Phenylalanine Hydroxylase and Tyrosine Aminotransferase in Human Fetal and Adult Liver

Cited by 20 publications

References 0 publications

The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Outcome of pregnancy in the rat with mild hyperphenylalaninaemia and hypertyrosinaemia: Implications for the management of “human maternal PKU”

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