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  • Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes.

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes.

The pharmacogenomics journal (2003-11-05)
P C Ho, F S Abbott, U M Zanger, T K H Chang
摘要

The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9(*)2 and CYP2C9(*)3 variants were less efficient than the CYP2C9(*)1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9(*)2 was due to a reduced Vmax, whereas, in the case of CYP2C9(*)3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9(*)2 and CYP2C9(*)3 genotypes may compromise hepatic VPA biotransformation.

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Supelco
丙戊酸, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
2-丙基戊酸
Supelco
丙戊酸标准液 溶液, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®

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