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


RESULTS
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%.


CONCLUSIONS
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.
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Xiao-Xia
XX
Hu
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Quan
Q
Zhou
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Tian
T
Lan
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Xiang-Xin
XX
Huang
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Bing-Qing
BQ
Liang
The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics Ministry of Health, Beijing, China.
Da-Peng
DP
Dai
The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics Ministry of Health, Beijing, China.
Jian-Ping
JP
Cai
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Guo-Xin
GX
Hu
D044466:Asian People / Q000235:genetics; D001711:Biotransformation; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003640:Dealkylation; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism
D011994:Recombinant Proteins; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6; C028787:N-desmethyltamoxifen
CYP2D6 polymorphism; allelic variants; drug metabolism; tamoxifen