RT Journal Article
SR Electronic
T1 Stereochemical studies on the beta-oxidation of valproic acid in isolated rat hepatocytes.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 580
OP 586
VO 21
IS 4
A1 M A Shirley
A1 P Hu
A1 T A Baillie
YR 1993
UL http://dmd.aspetjournals.org/content/21/4/580.abstract
AB Stereochemical aspects of the biotransformation of valproic acid (VPA) to four compounds believed to represent products of mitochondrial beta-oxidation, viz. delta 2(E)-VPA, delta 3-VPA, 3-hydroxy-VPA, and 3-oxo-VPA, were examined in freshly isolated rat hepatocytes. Following incubation of the individual enantiomers of [5-13C]VPA and analysis of products by GC/MS techniques, it was possible to determine for each metabolite the relative populations of molecules that had been formed by oxidation on the pro-R vs. the pro-S propyl group of the drug. Metabolism was found to exhibit a slight preference (approximately 1.3:1) for attack on the pro-S side-chain for all four compounds, consistent with the hypothesis that this group shares a common metabolic origin. In contrast, the hepatotoxic terminal olefin, delta 4-VPA, was formed with marked enantiotopic differentiation (approximately 3.8:1) favoring the pro-R side-chain. The reason for the surprisingly low stereo-selectivity displayed by the products of beta-oxidation was investigated with the aid of [3-2H] delta 2(E)-VPA as metabolic substrate. Following incubation with rat hepatocytes, 35% of the substrate remaining after 2 hr was found to have been isomerized to [3'-2H] delta 2(E)-VPA. Because delta 2(E)-VPA is known to be formed from VPA-CoA through the action of 2-methyl-branched-chain acyl-CoA dehydrogenase, it is proposed that the three-carbon side-chains of both parent drug and delta 2(E)-VPA are interconverted as a consequence of reversibility in the second half-reaction of this enzymatic process.