The regulation of phenylalanine hydroxylase in rat tissues in vivo. The maintenance of high plasma phenylalanine concentrations in suckling rats: a model for phenylketonuria

Delvalle, J A; Greengard, Olga

doi:10.1042/bj1540613

Cited by 19 publications

(10 citation statements)

References 20 publications

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“…The significant difference between day 21 control and PA rats in the trends of daily body weight increments (from days 3 to 21) reaffirms earlier reports of retarded body growth in rats subjected to experimental PKU [5,27], A 20% decrease in mean body weight ( fig. 1) between control and PA rats at day 21 is in contrast to the 60% decrease noted at day 20 in rats undernourished from birth [22], Hence the body weight deficits in the PA rats are more likely to reflect the effects of PA treatment than of undernour ishment.…”

Section: Somatic Considerationssupporting

confidence: 88%

A Quantitative Ultrastructural Study of the Effects of Phenylacetate on Synaptic Organization in the Developing Rat Cerebral Cortex

Oorschot¹,

Jones²

1983

Dev Neurosci

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Male rats were injected with either phenylacetate (PA; a phenylalanine metabolite) or saline (control). Osmicated tissue from the parietal cortex was analyzed qualitatively and quantitatively, attention being focused on possible synaptic changes in the molecular layer. PA-treated rats differed from controls in the following ways: a 20% decrease in body weight at 21 days, and a reduction in brain weight at 10 and 21 days; the presence of 'atypical' profiles (possibly derived from axonal growth cones) in the neuropil; a lag in the accretion of synapses per 100 μm² of tissue, and of vesicles per μm²of presynaptic terminal; the presence of a 'crossover' in the developmental trend for several synaptic organizational parameters between days 15 and 21; an elevation in synaptic density at day 21; an increased proportion of negatively curved synapses at 21 days; a significant difference in the preponderance of axodendritic synapses over days 7–21. This suggests that the metabolism of some neurons in the PA brain is initially different from normal, with a lag in synaptic development being evident. The increase in synaptic density and the relative preponderance of other synaptic parameters at 21 days signifies that an initial lag in development may alter the developmental scheme. This may be coupled with changes in synaptic efficacy and connectivity.

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Section: Somatic Considerationssupporting

confidence: 88%

A Quantitative Ultrastructural Study of the Effects of Phenylacetate on Synaptic Organization in the Developing Rat Cerebral Cortex

Oorschot¹,

Jones²

1983

Dev Neurosci

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“…Although subcutaneous or intraperitoneal injections of phenylalanine plus cr-methylphenylalanine have been our usual method of inducing severe hyperphenylalaninemia (12,21,25), some observations on 22-33-day-old rats indicated that similar results could be obtained by the incorporation of these substances into solid food (11). To avoid daily injections, this diet (see "Materials and Methods") was given to pregnant rats.…”

Section: Resultsmentioning

confidence: 99%

“…The assay of hepatic phenylalanine hydroxylase (E.C. 1.14.16.1) was as described by DelValle and Greengard (12). Protein was measured by the method of Lowry, et a1 (34) and DNA by the procedure of Kissane and Robins (27) as modified by Hinegardner (23).…”

Section: Animalsmentioning

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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“…served the practical purpose of creating hyperphenylrelationship between the amount of ingested phenylalaninaemic rats are described-in the preceding paper alanine and the concentration of this enzyme; they (DelValle & Greengard, 1976). reported that -in rats maintained on a low phenyl-McGee et aL.…”

mentioning

confidence: 99%

“…prompted-.by an. accidental observation; in experiments designed to maintain high concentrations of MaealanMthd phenylalanine in the plasma of immature rats [see the MaeilanMthd preceding paper (DelValle & Greengard, 1976)] we The animals used and the preparation of the noted that the recovery of phenylalanine hydroxylase phenylalanine and p-chlorophenylalanine suspension after inhibition by p-chlorophenylalanine in vivo was to be injected were as described in the precedinig'pape greatly hastened by injections of phenylalanine.…”

mentioning

confidence: 99%

The regulation of phenylalanine hydroxylase in rat tissues in vivo. Substrate- and cortisol-induced elevations in phenylalanine hydroxylase activity

Greengard

Delvalle

1976

Biochemical Journal

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Injections of phenylalanine increased a 2.5-fold in 9 h the hepatic phenylalanine hydroxylase activity of 6-day-old or adult rats that had been pretreated (24h earlier) with p-chlorophenylalanine; without such pretreatment, phenylalanine did not raise the enzyme concentration. This difference is paralleled by the much greater extent to which the injected phenylalanine accumulated in livers of the pretreated compared with the normal animals. The hormonal induction of hepatic phenylalanine hydroxylase activity obeyed different rules: an injection of cortisol was without effect on adult livers but caused a threefold rise in phenylalanine hydroxylase activity of immature ones, both without and after pretreatment with p-chlorophenylalanine. In the latter instance, the effects of cortisol, and of phenylalanine were additive. Actinomycin inhibited the cortisol- but not the substrate-induced increase of phenylalanine hydroxylase, whereas puromycin inhibited both. The results indicate that substrate and hormone, two potential positive regulators of the amount of the hepatic (but not the renal) phenylalanine hydroxylase, act independently by two different mechanisms. The negative effector, p-chlorophenylalanine, also appears to interact with the synthetic (or degradative) machinery rather than with the existing phenylalanine hydroxylase molecules: 24h were required in vivo for an 85% decrease to ensue, and no inhibition occurred in vitro when incubating the enzyme with p-chlorophenylalanine or with liver extracts from p-chlorophenylalanine-treated rats.

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The regulation of phenylalanine hydroxylase in rat tissues in vivo. The maintenance of high plasma phenylalanine concentrations in suckling rats: a model for phenylketonuria

Cited by 19 publications

References 20 publications

A Quantitative Ultrastructural Study of the Effects of Phenylacetate on Synaptic Organization in the Developing Rat Cerebral Cortex

A Quantitative Ultrastructural Study of the Effects of Phenylacetate on Synaptic Organization in the Developing Rat Cerebral Cortex

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

The regulation of phenylalanine hydroxylase in rat tissues in vivo. Substrate- and cortisol-induced elevations in phenylalanine hydroxylase activity

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