Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-desmethyltamoxifen 4-hydroxylation activity

Yuka Muroi, Takahiro Saito, Masamitsu Takahashi, Kanako Sakuyama, Yui Niinuma, Miyabi Ito, Chiharu Tsukada, Kiminori Ohta, Yasuyuki Endo, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)


Genetic variations in cytochrome P450 2D6 (CYP2D6) contribute to interindividual variability in the metabolism of clinically used drugs, e.g., tamoxifen. CYP2D6 is genetically polymorphic and is associated with large interindividual variations in therapeutic efficacy and drug toxicity. In this study, we performed an in vitro analysis of 50 allelic variants of CYP2D6 proteins. Wild-type CYP2D6.1 and 49 variants were transiently expressed in COS-7 cells, and the enzymatic activities of the CYP2D6 variants were characterized using N-desmethyltamoxifen as a substrate. The kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyltamoxifen 4-hydroxylation were determined. Among the 50 CYP2D6 variants, the kinetic parameters for N - desmethyltamoxifen 4-hydroxylation were determined for 20 CYP2D6 variants. On the other hand, the kinetic parameters of 30 CYP2D6 variants could not be determined because the amount of metabolite produced was at or below the detection limit at the lower substrate concentrations. Among them, 8 variants, i.e., CYP2D6.2, .9, .26, .28, .32, .43, .45, and .70, showed decreased intrinsic clearance at <50% of CYP2D6.1. The comprehensive in vitro assessment of CYP2D6 variants provides novel insights into allele-specific activity towards tamoxifen and may be valuable when interpreting in vivo studies.

Original languageEnglish
Pages (from-to)360-366
Number of pages7
JournalDrug Metabolism and Pharmacokinetics
Issue number5
Publication statusPublished - 2014


  • CYP2D6
  • Cytochrome P450
  • Drug metabolism
  • Genetic polymorphisms
  • Pharmacogenomics
  • Tamoxifen


Dive into the research topics of 'Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-desmethyltamoxifen 4-hydroxylation activity'. Together they form a unique fingerprint.

Cite this