title: Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57).
abstract: 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.
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Sakuyama
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Shuta
authors.initials: S
authors.lastname: Ujiie
authors.forename: Kanako
authors.initials: K
authors.lastname: Obata
authors.forename: Michinao
authors.initials: M
authors.lastname: Mizugaki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiratsuka
mesh_terms: D000818:Animals; D019556:COS Cells; D002384:Catalysis; D002522:Chlorocebus aethiops; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D006801:Humans; D007564:Japan; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000502:physiology*; D014162:Transfection
chemical_list: D004983:Ethanolamines; D003915:Dextromethorphan; C010831:bufuralol; D019389:Cytochrome P-450 CYP2D6