The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes

Tamoxifen, a typical therapy for cancer of the breast, is metabolized to compounds with anti-estrogenic in addition to oestrogen-like action in the oestrogen receptor. Little is famous concerning the formation of oestrogen-like metabolites as well as their biological impact. Thus, we characterised the oestrogen-like metabolites tamoxifen bisphenol and metabolite E for his or her metabolic path as well as their affect on cytochrome P450 activity and ADME gene expression. The development of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolic process and effect on CYP enzymes was examined in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and oestrogen-like metabolites on CYP activity was measured by HPLC MS/MS as well as on ADME gene expression using RT-PCR analyses. Metabolite E was created from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly created from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, correspondingly. Regarding phase II metabolic process, UGT2B7, 1A8 and 1A3 demonstrated greatest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the game of CYP2C enzymes while tamoxifen bisphenol consistently caused CYPs much like rifampicin and phenobarbital. Around the transcript level, greatest induction as much as 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Oestrogen-like tamoxifen metabolites are created in CYP-dependent reactions and therefore are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and also the inhibition of CYP2C enzymes by anti-estrogenic metabolites can lead to drug-drug-interactions.