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Drug Metabolism and Disposition Fast Forward
First published on September 10, 2008; DOI: 10.1124/dmd.108.023242

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Received for publication July 7, 2008.
Revised September 4, 2008.
Accepted for publication September 8, 2008.

Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57)

Kanako Sakuyama 1, Takamitsu Sasaki 1, Shuta Ujiie 1, Kanako Obata 1, Michinao Mizugaki 1, Masaaki Ishikawa 1, Masahiro Hiratsuka 1*

1 Tohoku Pharmaceutical University

* Address correspondence to: E-mail: mhira{at}tohoku-pharm.ac.jp

Abstract

Cytochrome P450 2D6 (CYP2D6) is an enzyme of potential importance for the metabolism of clinically used drugs, and it exhibits genetic polymorphism with interindividual differences in metabolic activity. To date, 21 CYP2D6 allelic variants have been identified in the Japanese population. The aim of this study was to investigate the functional characterization of CYP2D6 variants identified in Japanese subjects. Wild-type CYP2D6 and its variants, namely, CYP2D6.2, CYP2D6.10, CYP2D6.14A, CYP2D6.14B, CYP2D6.18, CYP2D6.27, CYP2D6.36, CYP2D6.39, CYP2D6.47, CYP2D6.48, CYP2D6.49, CYP2D6.50, CYP2D6.51, CYP2D6.53, CYP2D6.54, CYP2D6.55 and CYP2D6.57 were transiently expressed in COS-7 cells, and enzymatic activities of the CYP2D6 variant proteins were characterized using bufuralol and dextromethorphan. Functional characterization of 17 CYP2D6 variants revealed an absence of enzyme activity in 4 (CYP2D6.14A, CYP2D6.36, CYP2D6.47, and CYP2D6.57), low activity in 8 (CYP2D6.10, CYP2D6.14B, CYP2D6.18, CYP2D6.49, CYP2D6.50, CYP2D6.51, CYP2D6.54, and CYP2D6.55) and high activity in 1 (CYP2D6.53) as compared with the wild-type. Analysis of CYP2D6 variant proteins can be useful for predicting CYP2D6 phenotypes and could be applied to personalized drug therapy.


Key words: CYP2D, cytochrome P450 function, human CYP enzymes, human genetics, pharmacogenetics, pharmacogenomics, polymorphisms


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