Metabolism of valproic acid by hepatic microsomal cytochrome P-450.
Incubation of valproic acid with rat liver microsomes led to the formation of 3-, 4- and 5-hydroxy-valproic acid. The latter two metabolites, which have been characterized previously from in vivo studies, may be regarded as products of fatty acid omega-1 and omega hydroxylation, respectively. 3-Hydroxy-valproic acid, however, had been thought to derive from the beta-oxidation pathway in mitochondria. Conversion of valproic acid to all three metabolites in microsomes required NADPH (NADH was less effective), utilized molecular oxygen, was suppressed by inhibitors of cytochrome P-450 and was stimulated (notably at C-3 and C-4) by phenobarbital pretreatment of the rats. It is concluded that rat liver microsomal cytochrome P-450 catalyzes omega-2 hydroxylation of valproic acid, a reaction not detected previously with fatty acids in mammalian systems, and that the product, 3-hydroxy-valproic acid, should not be used to assess in vivo metabolism of valproate via the beta-oxidation pathway.
D000693:Anaerobiosis; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010103:Oxygen Isotopes; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000378:metabolism*
D010103:Oxygen Isotopes; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010634:Phenobarbital; D008797:Metyrapone