Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan

Hypertens Res. 2008 Aug;31(8):1549-57. doi: 10.1291/hypres.31.1549.

Abstract

CYP2C9, a drug-metabolizing enzyme, converts the angiotensin II receptor blocker losartan to its active form, which is responsible for its antihypertensive effect. We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients under treatment with losartan. Of two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance toward diclofenac when expressed in a baculovirus-insect cell system, while the Arg335Gln variant had no substantial effect. Several known missense variations were also found, and approximately 7% of the Japanese individuals (53 out of 724) carried one of the deleterious alleles (CYP2C9*3, *13, *14, *30, and Arg132Gln) as heterozygotes. After 3 months of losartan treatment, systolic blood pressure was not lowered in two patients with CYP2C9* 1/*30, suggesting that they exhibited impaired in vivo CYP2C9 activity. CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / therapeutic use*
  • Aryl Hydrocarbon Hydroxylases / chemistry
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Asian Continental Ancestry Group / genetics
  • Crystallography
  • Cytochrome P-450 CYP2C9
  • Drug Resistance / genetics
  • Female
  • Genetic Variation
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / ethnology
  • Hypertension / genetics*
  • Losartan / pharmacokinetics
  • Losartan / therapeutic use*
  • Male
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary

Substances

  • Antihypertensive Agents
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Losartan