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Drug Metabolism and Disposition Fast Forward
First published on June 18, 2009; DOI: 10.1124/dmd.109.027003

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Received for publication February 5, 2009.
Revised June 14, 2009.
Accepted for publication June 15, 2009.

Substrate-dependent functional alterations of seven CYP2C9 variants found in Japanese subjects

Keiko Maekawa 1*, Noriko Harakawa 1, Emiko Sugiyama 1, Masahiro Tohkin 1, Su-Ryang Kim 1, Nahoko Kaniwa 1, Noriko Katori 1, Ryuichi Hasegawa 1, Kazuki Yasuda 2, Kei Kamide 3, Toshiyuki Miyata 4, Yoshiro Saito 1, Jun-ichi Sawada 1

1 National Institute of Health Sciences 2 International Medical Center of Japan 3 Osaka University Graduate School of Medicine 4 National Cardiovascular Center

* Address correspondence to: E-mail: maekawa{at}nihs.go.jp

Abstract

Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme which metabolizes a number of clinically important drugs. In this study, catalytic activities of seven alleles found in Japanese individuals, CYP2C9*3 (Ile359Leu), *13 (Leu90Pro), *26 (Thr130Arg), *28 (Gln214Leu), *30 (Ala477Thr), *33 (Arg132Gln) and *34 (Arg335Gln), were assessed using three substrates, diclofenac, losartan and glimepiride. When expressed in a baculovirus-insect cell system, the holo- and total (apo- and holo-) CYP2C9 protein expression levels were similar among the wild-type (CYP2C9.1) and 6 variants except for CYP2C9.13. A large part of CYP2C9.13 was present in the apo-form P420. As compared with CYP2C9.1, all variants except for CYP2C9.34 exhibited substrate-dependent changes in Km, Vmax and intrinsic clearance (Vmax/Km). For diclofenac 4'-hydroxylation, the intrinsic clearance was decreased markedly (by >80%) in CYP2C9.13, CYP2C9.30 and CYP2C9.33 and variably (63 - 76%) in CYP2C9.3, CYP2C9.26 and CYP2C9.28 due to increased Km and/or decreased Vmax values. As for losartan oxidation, CYP2C9.13 and CYP2C9.28 showed 2.5- and 1.8-fold higher Km values, respectively, and all variants except for CYP2C9.34 showed >77% lower Vmax and intrinsic clearance values. For glimepiride hydroxylation, Km of CYP2C9.13 was increased 7-fold, and the Vmax values of all variants significantly decreased, resulting in reductions in the intrinsic clearance by >80% in CYP2C9.3, CYP2C9.13, CYP2C9.26 and CYP2C9.33 and by 56 - 75% in CYP2C9.28 and CYP2C9.30. These findings suggest the necessity for careful administration of losartan and glimepiride to patients bearing these 6 alleles.


Key words: CYP2C, cytochrome P450 catalyzed oxidations, enzyme kinetics, microsomes, pharmacogenetics, recombinant proteins




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