Effect of aromatic ring–containing drugs on carnitine biosynthesis in rats with special regard to p-aminomethylbenzoic acid

• Published in: Metabolism, clinical and experimental Vol. 54; no. 12; pp. 1582 - 1586
• Main Authors: Debreceni, Balazs, Farkas, Viktoria, Fischer, Gabor M., Sandor, Attila
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.12.2005; Elsevier
• Subjects: 4-Aminobenzoic Acid - pharmacology; Animals; Betaine - analogs & derivatives; Betaine - metabolism; Biological and medical sciences; Carnitine - biosynthesis; Carnitine - metabolism; Hydroxylation; Ketoglutaric Acids - metabolism; Male; Medical sciences; Metabolic diseases; para-Aminobenzoates; Rats; Rats, Wistar; Drug; Vertebrata; Mammalia; Acids; Rat; Aminoacid; Animal; Rodentia; Biosynthesis; Carnitine
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2005.06.004

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 γ-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- 3H]Bu to [Me- 3H]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 μmol/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 ( α-KG), an obligatory cofactor of the enzyme, was also be depressed. It was expected because α-KG is a reversible copartner of l-glutamate through the Glu-dehydrogenase reaction. We found that PAMBA reduced the α-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.