The Effect of Tamoxifen Metabolism Enzymes Pharmocogenetics on Breast Cancer

来源 :中国上海第七届国际新药发明科技年会 | 被引量 : 0次 | 上传用户:horse12
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  The nonsteroidal antiestrogen tamoxifen is an adjuvant chemotherapeutic agent used extensively for the treatment and chemoprevention of breast cancer.However,there are large variations among patients in both the therapeutic efficacy and side effects of this drug.Pharmacogenetics and pharmacogenomics is the study of the role of inheritance in this variation,genetic variation in tamoxifen response represents one of the most striking examples of the potential clinical importance of pharmacogenetics and pharmacogenomics.Tamoxifen requires "metabolic activation" catalyzed by cytochrome P450 2D6 (CYP2D6) to form hydroxylated metabolites-4-hydroxytamoxifen and endoxifen (N-desmethyl-4-hydroxytamoxifen),both are more than 100 times potent than the parent drug.The cytochrome P450 3A4 and cytochrome P450 3A5 (CYP3A4 and CYP3A5) are the major catalysts ofN-demethylation.Cis-4-hydroxy-tamoxifen has in addition been reported to exist at higher concentrations than trans-4-hydroxy-tamoxifen in patients with breast cancer with acquired resistance to tamoxifen.The sulphation of trans-4-hydroxy-tamoxifen and the glucuronidation of cis-4-hydroxy-tamoxifen,are catalysed by sulphotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 2B 15 (UGT2B 15),respectively.However,the polymorphisms of these enzymes affect the metabolic activation and the efficacy of Tamoxifen.The polymorphisms of CYP2D6 (CYP2D6* 1 and * 10),CYP3A5 (CYP3A5*1 and *3),SULT1A1 (SULT1Al*1 and *2) and UGT2B15 (UGT2B15*l and *2) are examined in tamoxifen-treated patients with Chinese breast cancer patients,and discern whether the genotypes correlated with clinical efficacy and side effects of tamoxifen.
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