Metabolism of unsaturated derivatives of valproic acid in rat liver microsomes and destruction of cytochrome P-450.

2-n-Propyl-4-pentenoic acid (delta 4-VPA), an unsaturated metabolite of valproic acid (VPA), and the ethyl ester of delta 4-VPA were tested for their ability to cause NADPH- and time-dependent loss of cytochrome P-450 in hepatic microsomal preparations from phenobarbital-pretreated rats. Ethyl delta 4-VPA gave a large amount of destruction (33 +/- 4% over 30 min), whereas delta 4-VPA was a much less effective inhibitor of the enzyme (8 +/- 2% destruction over 30 min). This difference in degree of enzyme loss correlated well with the respective rates at which the substrates underwent oxidative metabolism of the terminal double bond. It is likely, therefore, that the mechanism of action of these compounds is the same as that for allylisopropylacetamide (AIA) and related monosubstituted olefins, which are converted by cytochrome P-450 to chemically reactive species which bind covalently to the prosthetic heme moiety of the cytochrome and thereby destroy the enzyme. In microsomes, both delta 4-VPA and its ethyl ester were metabolized by cytochrome P-450 to a common cyclic end-product, 3-n-propyl-5-hydroxymethyltetrahydro-2-furanone, although stable isotope labeling experiments with oxygen-18 demonstrated that the pathways followed by the two substrates were mechanistically distinct. These findings, together with data from related metabolic studies on AIA, support the view that the efficiency of the initial double bond oxidation reaction determines the extent of cytochrome P-450 destruction during the metabolism of terminal olefins, rather than any subsequent step.(ABSTRACT TRUNCATED AT 250 WORDS)