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

Abstract

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.

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

“…Other enzymes involved in tamoxifen metabolism comprise CYP2C9, CYP2C19, and CYP2B6 [13]. These three enzymes are also involved in the formation of 4-OH-tamoxifen and endoxifen, but their contribution may depend on actual tamoxifen concentrations and on CYP2D6 activity.…”

Pharmacogenetic testing of allelic variants of the CYP2D6 gene in hormone positive breast cancer

“…По разным данным, у больных гормоноположительным РМЖ при приеме тамоксифена в стандартной дозе 20 мг / сут кон-центрация 4-гидрокситамоксифена составляет 10-20 % от концентрации эндоксифена, который при-мерно в 100 раз легче связывается с рецепторами эстрогенов, чем его предшественники [13][14][15][16].…”

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

“…CYP2D6 activity is highly associated with TAM metabolism and may affect clinical activity. 11,12 Coincubation of TAM with potent, specific CYP2D6 chemical inhibitors such as quinidine and the antidepressant paroxetine confirmed that the inhibition of CYP2D6 activity prevents the formation of the important metabolite endoxifen. However, because TOR is less subject to CYP2D6-mediated hydroxylation, these inhibitors had little effect on the metabolism of TOR in our assays.…”

“…1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. …”

“…1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. [13][14][15][16] Whether these metabolites are responsible for TAM's variable clinical efficacy is a topic of considerable controversy.…”