Functional characterization of 22 novel CYP2D6 variants for the metabolism of Tamoxifen.

OBJECTIVES

This study aimed to assess the catalytic characteristics of 24 CYP2D6 allelic isoforms found in Chinese Han population on the metabolism of tamoxifen in vitro.

METHODS

Recombinant CYP2D6 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity towards tamoxifen. About 5-2500 μm tamoxifen was incubated for 30 min at 37 °C. Using high-performance liquid chromatography to detect the products, the kinetic parameters Km , Vmax and intrinsic clearance (Vmax /Km ) of N-desmethyltamoxifen were determined.

KEY FINDINGS

Of the 24 tested allelic variants, the differences of intrinsic clearance value were shown as follows: CYP2D6.89 was much higher than wild-type CYP2D6.1, 2 allelic isoforms (CYP2D6.88 and D336N) exhibited similar intrinsic clearance values as the wild-type enzyme, two variants displayed weak or no activity, while the rest 19 variants showed significantly reduced intrinsic clearance values ranging from 7.46 to 81.11%.

CONCLUSION

The comprehensive assessment of CYP2D6 variants provides significant insights into allele-specific activity towards tamoxifen in vitro, suggesting that most of the carriers of these alleles might be paid more attention when using CYP2D6-mediated drugs clinically.