EFFECT OF VALPROIC ACID ON GLYCINE CONJUGATION OF BENZOIC-ACID

Conjugation with glycine proceeds through ATP-dependent coupling of ca rboxylic acids with coenzyme A (CoA). Therefore, chemicals that form C oA esters may interfere with glycine conjugation. We tested the hypoth esis that valproic acid (VPA), which is esterified with CoA in the fir st step of its mitochondrial beta-oxidation, may compromise glycine co njugation of aromatic carboxylic acids, by investigating the effect of acute VPA administration on glycine conjugation of benzoic acid in ra ts. VPA administered 1 hr before injection of benzoate only decreased the blood clearance of benzoate and the urinary excretion of benzoylgl ycine 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 an d 59%, diminished the peak blood level of the glycine conjugate and de pressed the maximal urinary excretion rate of benzoylglycine by 28 and 66%, respectively. To elucidate the mechanism of VPA-induced inhibiti on of benzoylglycine formation, the effects of VPA on hepatic levels o f cosubstrates and the activities of enzymes involved in glycine conju gation were also determined. One hour after administration of VPA, hep atic ATP levels remained unchanged, whereas the concentration of CoA w as 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, in hibited benzoyl-CoA synthetase. In summary, VPA minimally influenced t he capacity of glycine conjugation of benzoic acid in normal rats, but decreased it markedly in glycine-loaded rats. This apparently results from the VPA-induced increase in hepatic glycine (possibly due to inh ibition of the glycine cleavage system), which would facilitate format ion of benzoylglycine and thereby counteract in part the inhibitory ef fect of VPA on the glycine conjugation of benzoic acid. VPA may inhibi t glycine conjugation by reducing CoA availability and/or inhibiting a cyl-CoA synthetase. The latter effect is apparently exerted by a metab olite, such as 2-n-propyl-4-pentenoic acid.