Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anticonvulsive drug, valproic acid (VPA), inhibits the biosynthesis of carnitine, and may contribute in this way to carnitine deficiency associated with VPA therapy. The conversion of [3H]-butyrobetaine into [3H]-carnitine was determined 60 min following a single intraperitoneal (i.p.) dose of 1.2 mmol/kg VPA in rats. The fraction of radioactivity found in [3H]-carnitine in the liver decreased from 63.2 +/- 1.50% to 39.2 +/- 1.11% (mean +/- SEM). Total carnitine in the liver also decreased, whereas the precursor butyrobetaine increased from 5.01 +/- 0.71 nmol/g to 8.22 +/- 0.82 nmol/g (mean +/- SEM). VPA also exhibited a dramatic effect on the conversion of an unlabeled loading amount of butyrobetaine. The increment in total carnitine caused by butyrobetaine in liver was reduced from 161 +/- 15.4 nmol/g to 53.2 +/- 5.11 nmol/g (mean +/- SEM). These data prove that VPA reduces the flux through butyrobetaine hydroxylase (EC 1.14.11.1.). The drug in vitro, however, did not inhibit the enzyme directly. Searching for the mechanism of action, we found that VPA decreased the level of alpha-ketoglutarate (alpha-KG; a cofactor of butyrobetaine hydroxylase) from 73.5 +/- 2.90 nmol/g to 52.9 +/- 2.2 nmol/g (mean +/- SEM) in the liver. The level of 1-glutamate showed a rather dramatic decrease in the liver. Moreover, alpha-KG proved to have a protective role against VPA in the [3H]-butyrobetaine conversion experiment.
 ...
PMID:Inhibition of carnitine biosynthesis by valproic acid in rats--the biochemical mechanism of inhibition. 893 54

Secondary carnitine deficiencies are associated with metabolic disorders or may be the consequence of the side effects of some drugs. The mechanisms may be either a facilitated urinary excretion or an inhibited biosynthesis. Based on our earlier findings with drugs and benzoic acid analogue metabolites, in the present study, we studied the possible inhibitory effect of some benzoic acid analogue drugs. In the pathway of carnitine biosynthesis, we tested the last step, the hydroxylation of gamma-butyrobetaine (Bu) to carnitine in the liver. (Liver is the only organ in rats where this step takes place.) Of the 5 tested compounds, the p-aminomethylbenzoic acid (PAMBA) was found to be inhibitory. In tracer experiments with radioactive Bu, PAMBA (a single injection of 1.2 mmol/kg) reduced the conversion of [Me-(3)H]Bu to [Me-(3)H]carnitine from 62.6% +/- 5.11% to 46.8% +/- 5.02% (means +/- SEM, P < .02). This single dose also markedly reduced the conversion of loading amount of exogenous unlabeled Bu, as measured by enzymatic analysis of carnitine. The conversion of endogenous Bu was also hampered by long-term administration of PAMBA, as indicated by increased Bu and decreased carnitine levels. Furthermore, single injection of PAMBA markedly reduced the Glu level in the liver from 2.87 +/- 0.17 to 1.42 +/- 0.11 mumol/g (P < .001). Trying to get closer to a mechanism by which the flux through the Bu hydroxylase was depressed, we supposed that alfa-ketoglutarate (alpha-KG), an obligatory cofactor of the enzyme, was also be depressed. It was expected because alpha-KG is a reversible copartner of l-glutamate through the Glu-dehydrogenase reaction. We found that PAMBA reduced the alpha-KG level from 207 +/- 17.5 to 180 +/- 19.1 nmol/g (means +/- SEM, P < .02). Considering the conditions of the enzyme in vitro and in vivo, this decrease may contribute to the decreased in vivo flux through the butyrobetaine hydroxylase enzyme.
 ...
PMID:Effect of aromatic ring-containing drugs on carnitine biosynthesis in rats with special regard to p-aminomethylbenzoic acid. 1631 Oct 89