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

Pharmacogenomics J. 2003;3(6):335-42. doi: 10.1038/sj.tpj.6500210.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cytochrome P-450 CYP2C9
  • Genotype
  • Humans
  • Insecta
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Valproic Acid / metabolism*
  • Valproic Acid / toxicity*


  • Valproic Acid
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases