Functional Characterization of 17 CYP2D6 Allelic Variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57)

• Published in: Drug metabolism and disposition Vol. 36; no. 12; pp. 2460 - 2467
• Main Authors: Sakuyama, Kanako, Sasaki, Takamitsu, Ujiie, Shuta, Obata, Kanako, Mizugaki, Michinao, Ishikawa, Masaaki, Hiratsuka, Masahiro
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.12.2008; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Animals; Biological and medical sciences; Catalysis; Chlorocebus aethiops; COS Cells; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Dextromethorphan - metabolism; Ethanolamines - metabolism; Humans; Japan; Kinetics; Medical sciences; Microsomes - metabolism; Pharmacology. Drug treatments; Polymorphism, Genetic - physiology; Transfection; Japan; Characterization; Variant; Genetic variability; Enzyme; Isozyme; Cytochrome P450; Genotype
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.108.023242

Cytochrome P450 2D6 (CYP2D6) is an enzyme of potential importance for the metabolism of drugs used clinically, 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 four (CYP2D6.14A, CYP2D6.36, CYP2D6.47, and CYP2D6.57), low activity in eight (CYP2D6.10, CYP2D6.14B, CYP2D6.18, CYP2D6.49, CYP2D6.50, CYP2D6.51, CYP2D6.54, and CYP2D6.55), and high activity in one (CYP2D6.53) 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.