TY - JOUR
T1 - Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan
AU - Yin, Tong
AU - Maekawa, Keiko
AU - Kamide, Kei
AU - Saito, Yoshiro
AU - Hanada, Hironori
AU - Miyashita, Kotaro
AU - Kokubo, Yoshihiro
AU - Akaiwa, Yasuhisa
AU - Otsubo, Ryoichi
AU - Nagatsuka, Kazuyuki
AU - Otsuki, Toshiho
AU - Horio, Takeshi
AU - Takiuchi, Shin
AU - Kawano, Yuhei
AU - Minematsu, Kazuo
AU - Naritomi, Hiroaki
AU - Tomoike, Hitonobu
AU - Sawada, Jun Ichi
AU - Miyata, Toshiyuki
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - CYP2C9
KW - Hypertension
KW - Losartan
KW - Single nucleotide polymorphism
UR - https://www.scopus.com/pages/publications/55449103747
U2 - 10.1291/hypres.31.1549
DO - 10.1291/hypres.31.1549
M3 - 記事
C2 - 18971529
AN - SCOPUS:55449103747
SN - 0916-9636
VL - 31
SP - 1549
EP - 1557
JO - Hypertension Research
JF - Hypertension Research
IS - 8
ER -