Abstract

Conjugation with glycine proceeds through ATP-dependent coupling of carboxylic acids with coenzyme A (CoA). Therefore, chemicals that form CoA esters may interfere with glycine conjugation. We tested the hypothesis that valproic acid (VPA), which is esterified with CoA in the first step of its mitochondrial beta-oxidation, may compromise glycine conjugation of aromatic carboxylic acids, by investigating the effect of acute VPA administration on glycine conjugation of benzoic acid in rats. VPA administered 1 hr before injection of benzoate only decreased the blood clearance of benzoate and the urinary excretion of benzoylglycine slightly in normal rats. However, in rats loaded with glycine, 2 and 3 mmol/kg of VPA reduced the blood clearance of benzoate by 34 and 59%, diminished the peak blood level of the glycine conjugate and depressed the maximal urinary excretion rate of benzoylglycine by 28 and 66%, respectively. To elucidate the mechanism of VPA-induced inhibition of benzoylglycine formation, the effects of VPA on hepatic levels of cosubstrates and the activities of enzymes involved in glycine conjugation were also determined. One hour after administration of VPA, hepatic ATP levels remained unchanged, whereas the concentration of CoA was reduced by 67 to 73% and that of glycine was increased by 58 to 67%. Activities of the enzymes of glycine conjugation were not influenced by VPA. However, 2-n-propyl-4-pentenoic acid, a metabolite of VPA, inhibited benzoyl-CoA synthetase. In summary, VPA minimally influenced the capacity of glycine conjugation of benzoic acid in normal rats, but decreased it markedly in glycine-loaded rats.(ABSTRACT TRUNCATED AT 250 WORDS)