Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma

Clin Pharmacol Ther. 2011 May;89(5):708-17. doi: 10.1038/clpt.2011.27. Epub 2011 Mar 30.


The therapeutic effect of tamoxifen depends on active metabolites, e.g., cytochrome P450 2D6 (CYP2D6) mediated formation of endoxifen. To test for additional relationships, 236 breast cancer patients were genotyped for CYP2D6, CYP2C9, CYP2B6, CYP2C19, CYP3A5, UGT1A4, UGT2B7, and UGT2B15; also, plasma concentrations of tamoxifen and 22 of its metabolites, including the (E)-, (Z)-, 3-, and 4'-hydroxymetabolites as well as their glucuronides, were quantified using liquid chromatography-tandem mass spectrometry (MS). The activity levels of the metabolites were measured using an estrogen response element reporter assay; the strongest estrogen receptor inhibition was found for (Z)-endoxifen and (Z)-4-hydroxytamoxifen (inhibitory concentration 50 (IC50) 3 and 7 nmol/l, respectively). CYP2D6 genotypes explained 39 and 9% of the variability of steady-state concentrations of (Z)-endoxifen and (Z)-4-hydroxytamoxifen, respectively. Among the poor metabolizers, 93% had (Z)-endoxifen levels below IC90 values, underscoring the role of CYP2D6 deficiency in compromised tamoxifen bioactivation. For other enzymes tested, carriers of reduced-function CYP2C9 (*2, *3) alleles had lower plasma concentrations of active metabolites (P < 0.004), pointing to the role of additional pathways.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aryl Hydrocarbon Hydroxylases / blood
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6 / blood
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 Enzyme System / blood
  • Cytochrome P-450 Enzyme System / genetics*
  • Female
  • Follow-Up Studies
  • Glucuronosyltransferase / blood
  • Glucuronosyltransferase / genetics*
  • Humans
  • Middle Aged
  • Polymorphism, Genetic / genetics*
  • Prospective Studies
  • Receptors, Estrogen / metabolism*
  • Tamoxifen / blood
  • Tamoxifen / chemistry
  • Tamoxifen / metabolism*


  • Receptors, Estrogen
  • bilirubin glucuronoside glucuronosyltransferase
  • Tamoxifen
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6
  • Glucuronosyltransferase