Metabolism of carnitine in phenylacetic acid-treated rats and in patients with phenylketonuria

The effect of metabolites accumulating in phenylketonuria (PKU) was investigated on carnitine metabolism in rats and in patients with PKU. Of phenylacetic acid (PEAA), phenylpyruvic acid and homogentisic acid the PEAA was found to be the most effective in inhibiting carnitine biosynthesis in rats. F...

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Published in:	Biochimica et biophysica acta Vol. 1501; no. 2; pp. 200 - 210
Main Authors:	Fischer, Gabor M., Nemeti, Balazs, Farkas, Viktoria, Debreceni, Balazs, Laszlo, Aranka, Schaffer, Zsuzsa, Somogyi, Csilla, Sandor, Attila
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 15-06-2000
Subjects:	Adult Animals Benzoic acid Betaine - analogs & derivatives Betaine - metabolism Carnitine Carnitine - analogs & derivatives Carnitine - analysis Carnitine - blood Carnitine - metabolism Carnitine - urine Female Glutamic Acid - metabolism Homogentisic Acid - pharmacology Humans Ketoglutaric Acids - metabolism Liver - drug effects Liver - metabolism Male Mass Spectrometry Phenacetylcarnitine Phenylacetate Phenylacetates - pharmacology Phenylketonuria Phenylketonurias - metabolism Phenylketonurias - urine Phenylpyruvic Acids - pharmacology PKU Rats Rats, Wistar Benzoic acid Phenylketonuria Phenylacetate α-KG, α-ketoglutarate Phenacetylcarnitine PEAA, phenylacetic acid PEAC, phenacetyl-carnitine PKU PKU, phenylketonuria Carnitine
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Summary:	The effect of metabolites accumulating in phenylketonuria (PKU) was investigated on carnitine metabolism in rats and in patients with PKU. Of phenylacetic acid (PEAA), phenylpyruvic acid and homogentisic acid the PEAA was found to be the most effective in inhibiting carnitine biosynthesis in rats. Following 60 min, a single intraperitoneal dose of PEAA the relative conversion rate, i.e. the hydroxylation, of tracer [Me- 3H]butyrobetaine to [Me- 3H]carnitine decreased from 62.2±6.00% to 39.4±5.11% (means±S.E.M., P<0.01) in the liver, in the only organ doing this conversion in rats. The conversion of loading amount of unlabeled butyrobetaine to carnitine was also markedly reduced. The impaired hydroxylation of butyrobetaine was reflected by a reduced free and total carnitine levels in the liver and a reduced total carnitine concentration in the plasma. PEAA decreased the hepatic level of glutamic acid and α-ketoglutaric acid (α-KG), suggesting a mechanism for the reduced flux through the butyrobetaine hydroxylase enzyme, because α-KG is an obligatory co-enzyme. In the plasma and urine of PKU patients on unrestricted diet, markedly decreased total carnitine levels were detected. In the liver of PEAA-treated rats and urine of PKU patients, a novel carnitine derivative, phenacetyl-carnitine was verified by HPLC and gas chromatography-mass spectrometry.
ISSN:	0925-4439 0006-3002 1879-260X
DOI:	10.1016/S0925-4439(00)00023-5