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|Title:||The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver|
|Citation:||British Journal of Clinical Pharmacology, 2002; 54(2):157-167|
|Publisher:||Blackwell Science Ltd|
|Janet K. Coller, Niels Krebsfaenger, Kathrin Klein, Karin Endrizzi, Renzo Wolbold, Thomas Lang, Andreas Nüssler, Peter Neuhaus, Ulrich M. Zanger, Michel Eichelbaum, Thomas E. Mürdter|
|Abstract:||Aims To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z-4-hydroxy-tamoxifen, and how various genotypes affect its formation from tamoxifen. Methods The formation of Z-4-hydroxy-tamoxifen from 10 µm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated. Z-4-hydroxy-tamoxifen was quantified using LC-MS analysis. Results Z-4-hydroxy-tamoxifen was formed by supersomes expressing CYP2B6, CYP2C9, CYP2C19 and CYP2D6, but not CYP3A4. In agreement with these data, the mean formation of Z-4-hydroxy-tamoxifen was inhibited 49% by sulphaphenazole (P=0.001), 38% by quinidine (P<0.05) and 13% by monoclonal antibody against CYP2B6 (MAB-2B6, P<0.05). Furthermore, Z-4-hydroxy-tamoxifen formation significantly correlated with both CYP2C9 expression (rs=0.256, P<0.05) and CYP2D6 expression (rs=0.309, P<0.05). Genotypes of CYP2D6, CYP2B6 and CYP2C9 had an effect on metabolite formation in such a way that samples with two nonfunctional CYP2D6, or two variant CYP2C9 or CYP2B6 alleles, showed lower enzyme activity compared with those with two functional or wild-type alleles, (5.0 vs 9.9 pmol mg1 protein min1, P=0.046, 5.1 vs 9.9 pmol mg1 protein min1, P=0.053, and 6.8 vs 9.4 pmol mg1 protein min1, P=0.054, respectively). CYP2D6 and CYP2C9 contribute on average 45 and 46%, respectively, to the overall formation of Z-4-hydroxy-tamoxifen. Conclusions CYP2B6, CYP2C9 and CYP2D6 genotypes all affected Z-4-hydroxy-tamoxifen formation and can predict individual ability to catalyse this reaction.|
|Keywords:||CYP2B6; CYP2C9; CYP2D6; genotype; Z-4-hydroxy-tamoxifen|
|Description:||The definitive version is available at www.blackwell-synergy.com|
|Appears in Collections:||Pharmacology publications|
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