Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan.
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.
Yin
Tong
T
Research Institute, Department of Medicine, National Cardiovascular Center, Suita, Japan.
Maekawa
Keiko
K
Kamide
Kei
K
Saito
Yoshiro
Y
Hanada
Hironori
H
Miyashita
Kotaro
K
Kokubo
Yoshihiro
Y
Akaiwa
Yasuhisa
Y
Otsubo
Ryoichi
R
Nagatsuka
Kazuyuki
K
Otsuki
Toshiho
T
Horio
Takeshi
T
Takiuchi
Shin
S
Kawano
Yuhei
Y
Minematsu
Kazuo
K
Naritomi
Hiroaki
H
Tomoike
Hitonobu
H
Sawada
Jun-ichi
J
Miyata
Toshiyuki
T
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
D000959:Antihypertensive Agents; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan