The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes
Autor: | Michel Eichelbaum, Astrid Nörenberg, Maria Thomas, Ulrich M. Zanger, Werner Schroth, Thomas E. Mürdter, Hiltrud Brauch, Matthias Schwab, Janina Johänning, Patrick Kröner |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
CYP2B6
Bisphenol Health Toxicology and Mutagenesis Metabolite Glucuronidation Estrogen receptor Gene induction Pharmacology Alkenes Toxicology 030226 pharmacology & pharmacy Gene Expression Regulation Enzymologic Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Glucuronides Cytochrome P-450 Enzyme System Phenols medicine Humans Glucuronosyltransferase skin and connective tissue diseases ADME CYP3A4 Estrogens General Medicine Tamoxifen Metabolism Estrogen-like metabolites chemistry 030220 oncology & carcinogenesis Hepatocytes Microsomes Liver hormones hormone substitutes and hormone antagonists CYP activity medicine.drug Toxicokinetics and Metabolism |
Zdroj: | Archives of Toxicology |
ISSN: | 1432-0738 0340-5761 |
Popis: | Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug–drug-interactions. Electronic supplementary material The online version of this article (10.1007/s00204-017-2147-y) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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