Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab


Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article


The Phase I metabolism of tamoxifen is extensive and involves several CYP450 DMEs including, but not limited to: CYP2D6, CYP2C9, CYP2C19, CYP2B6, CYP3A4 and CYP3A5 (Figure 1). As a prodrug, tamoxifen requires conversion into its primary metabolites, (Z)-4-hydroxytamoxifen ([Z]-4-OH-Tam) and N-desmethyltamoxifen (NDM-Tam). These metabolites are further converted into several secondary metabolites, including (Z)-4-hydroxy-N-desmethyltamoxifen, also known as endoxifen. Both (Z)-4-OH-Tam and endoxifen are shown to have significantly higher efficacy at the ER compared with the parent drug.[14,15] Furthermore, in vitro studies revealed that endoxifen inhibits estrogen-induced breast cancer cell proliferation depending on metabolite concentration.[16] CYP2D6 is involved in several steps of the metabolic pathway but is the only enzyme responsible for the specific conversion of NDM-Tam to endoxifen.[17,18] As steady-state plasma levels of endoxifen are approximately five-times higher than those of (Z)-4-OH-Tam and as endoxifen is the metabolite with lowest IC50 at the ER, it is currently perceived as the major active metabolite.[16,19]

Figure 1.

Major pathways of tamoxifen metabolism including the active metabolites and Phase II metabolism of (Z)-4-OH-Tam.

Tamoxifen and its metabolites are inactivated via glucuronidation and sulfation by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), respectively, and are eliminated mostly by biliary/fecal excretion.[20] Some of the major enzymes responsible for these inactivation steps include UGT1A4, UGT2B7, UGT2B15 and SULT1A1.