title: Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid.
abstract: The enantiomers of 2-[( 3-13C]-n-propyl)pentanoic acid [(R)- and (S)-[13C]VPA] were employed as metabolic probes to investigate stereochemical aspects of the biotransformation of valproic acid (VPA) to 2-n-propyl-4-pentenoic acid (delta 4-VPA), a hepatotoxic metabolite of VPA. When incubated with hepatocytes freshly isolated from untreated male rats, each labeled substrate (initial concentration 1.0 mM) underwent metabolism to [13C]-delta 4-VPA, the formation of which was time-dependent and occurred at a rate of ca. 20 ng/(10(6) cells.4-h incubation). Analysis of this unsaturated metabolite by GC-MS techniques revealed that, following incubation of (R)-[13C]VPA, desaturation had taken place preferentially (by a factor of approximately 4) on the labeled propyl group (i.e., on the R side chain). Parallel incubations with (S)-[13C]VPA supported this conclusion, in that metabolism of this isotopic variant of VPA led to a terminal olefin that also was predominantly (83 +/- 2%) of R configuration (in this case oxidized selectively on the unlabeled side chain). Hence, biotransformation of VPA to delta 4-VPA in rat hepatocytes occurs with marked enantiotopic differentiation, favoring production of the R enantiomer of this chiral metabolite. When rats were pretreated with phenobarbital (80 mg kg-1 day-1 ip for 3 days) prior to isolation of hepatocytes, the overall rate of metabolism of VPA to delta 4-VPA over the 4-h incubation period increased approximately 3-fold, while the degree of product enantioselectivity was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porubek
authors.forename: H
authors.initials: H
authors.lastname: Barnes
authors.forename: G P
authors.initials: GP
authors.lastname: Meier
authors.forename: L J
authors.initials: LJ
authors.lastname: Theodore
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
mesh_terms: D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014635:Valproic Acid / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D005229:Fatty Acids, Monounsaturated; C045022:2-propyl-4-pentenoic acid; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System