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

Arch Toxicol. 2018 Mar;92(3):1099-1112. doi: 10.1007/s00204-017-2147-y. Epub 2017 Dec 28.


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.

Keywords: CYP activity; Estrogen-like metabolites; Gene induction; Metabolism; Tamoxifen.

MeSH terms

  • Alkenes / pharmacokinetics
  • Cell Line
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Estrogens / pharmacokinetics
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucuronides / metabolism
  • Glucuronosyltransferase / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Phenols / pharmacokinetics
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / metabolism
  • Tamoxifen / pharmacokinetics*


  • Alkenes
  • Estrogens
  • Glucuronides
  • N,N-didesmethyl-4-hydroxytamoxifen
  • Phenols
  • Tamoxifen
  • afimoxifene
  • 4-hydroxy-N-desmethyltamoxifen
  • 1-(4-hydroxyphenyl)-1,2-diphenyl-1-butene
  • Cytochrome P-450 Enzyme System
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • UDP-glucuronosyltransferase, UGT1A8
  • N-desmethyltamoxifen