Δ2-Valproate biotransformation using human liver microsomal fractions
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The metabolism of 2-n-propyl-2-pentenoate (Δ2-VPA) was evaluated in human hepatic microsomal fractions. Two biotransformation pathways have been particularly investigated. In the presence of the cytochrome P-450 co-factor, NADPH, the main metabolites recovered were Δ3-VPA, Δ2,4-VPA and VPA. The glucuronidation of Δ2-VPA was also studied on various hepatic microsomal fractions using Brij® 35 as activator and UDP-glucuronic acid as co-factor. A large interindividual variability occurred in this metabolic pathway.K m andVmax were 0.85 mmol/l and 1.75 nmol·min−1·mg−1, respectively, for Δ2-VPA and 1.11 mmol/l and 5.71 nmol·min−1·mg−1 for VPA, respectively. The good correlationr=0.82; p<0.001) observed between the glucuronidation of VPA and Δ2-VPA as well as the mutual inhibition of each other's glucuronidation strongly suggests that (a) common single UDP-glucuronosyltransferase isoenzyme(s) was (were) involved in this glucuronidation step. The glucuronidation of specific substrates for various UDP-glucuronosyltransferase isoenzymes showed a good relationship between the glucuronidations of Δ2-VPA and morphine, a substrate for UDP-glucuronosyltransferase-2B. Moreover, morphine competitively inhibits A -VPA glucuronidation. It seems the same isoenzyme or, at least, (a) very closely related isoenzyme(s) belonging to UDP-glucuronosyltransferase-2 isoenzyme, is involved in Δ2-VPA glucuronidation.
KeywordsBiotransformation Cytochrome P-450 Isoenzymes Microsomes, liver 2-n-Propyl-2-pentenoic acid UDP glucuronosyltransferase Valproic acid
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