title: Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan.
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.
authors.affiliation: Research Institute, Department of Medicine, National Cardiovascular Center, Suita, Japan.
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hironori
authors.initials: H
authors.lastname: Hanada
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyashita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Akaiwa
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Otsubo
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nagatsuka
authors.forename: Toshiho
authors.initials: T
authors.lastname: Otsuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Shin
authors.initials: S
authors.lastname: Takiuchi
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minematsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Naritomi
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D003461:Crystallography; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D019808:Losartan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary
chemical_list: D000959:Antihypertensive Agents; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan