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Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan.
- Source :
-
Hypertension research : official journal of the Japanese Society of Hypertension [Hypertens Res] 2008 Aug; Vol. 31 (8), pp. 1549-57. - Publication Year :
- 2008
-
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.
- Subjects :
- Aged
Antihypertensive Agents pharmacokinetics
Aryl Hydrocarbon Hydroxylases chemistry
Aryl Hydrocarbon Hydroxylases metabolism
Asian People genetics
Crystallography
Cytochrome P-450 CYP2C9
Drug Resistance genetics
Female
Genetic Variation
Humans
Hypertension ethnology
Losartan pharmacokinetics
Male
Middle Aged
Mutation, Missense
Polymorphism, Single Nucleotide
Protein Structure, Tertiary
Antihypertensive Agents therapeutic use
Aryl Hydrocarbon Hydroxylases genetics
Hypertension drug therapy
Hypertension genetics
Losartan therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0916-9636
- Volume :
- 31
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Hypertension research : official journal of the Japanese Society of Hypertension
- Publication Type :
- Academic Journal
- Accession number :
- 18971529
- Full Text :
- https://doi.org/10.1291/hypres.31.1549