Glucuronidation of tamoxifen metabolites by UGTs. Potential role UGTs variants in tamoxifen metabolism

A154

Tamoxifen (TAM) is widely used in the treatment and prevention of breast cancer. trans-4-hydroxy-tamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyl-TAM (endoxifen) are the major active metabolites of TAM, exhibiting 100-fold higher anti-estrogenic activity than TAM itself, with endoxifen concentrations reaching plasma concentrations that are 6-12-fold higher than that of 4-OH-TAM. One of the major mechanisms of elimination of TAM and its metabolites is by glucuronidation. Previous studies have demonstrated that UGTs 2B7, 1A8 and 1A10 exhibited the highest overall O-glucuronidating activity against trans-4-OH-TAM and trans-endoxifen. While UGT1A10 also exhibited high overall O-glucuronidating activity against cis-4-OH-TAM and cis-endoxifen,UGT2B15 also demonstrated very high activity against these two metabolites. Previous studies demonstrated an association between N-glucuronidation activity against TAM and 4-OH-TAM by UGT1A4 variants; no studies have been performed for O-glucuronidating enzymes, and no studies have been performed on endoxifen. In the present study, the glucuronidating activities of polymorphic variants of these active UGTs were examined in vitro against isomers of both 4-OH-TAM and endoxifen. As compared to wild-type, the UGT1A10^139Lys, UGT2B7^268Tyr and UGT2B15^85Tyr variants exhibited significantly (p<0.02 for each) lower (1.6-7.8-fold) glucuronidating activities against cis-4-OH-TAM as determined by V_max/K_M; UGT2B7^268Tyr showed a significantly (p< 0.01) (2.4-fold) lower activity while UGT1A8^173Gly showed a significantly (p<0.05) (1.7-fold) higher glucuronidating activity against trans-4-OH-TAM. The UGT1A10^139Lys, UGT2B7^268Tyr and UGT1A8^173Gly variants exhibited significantly (p<0.05) lower (1.5-4.7-fold activity against cis-endoxifen; no detectable glucuronidation activity was observed for the UGT2B15^85Tyr variant against cis-endoxifen. UGT2B7^268Tyr exhibited a significantly (p<0.01) (5-fold) lower glucuronidating activity against trans-endoxifen. The UGT1A8^277Tyr variant exhibited no detectable glucuronidating activity against both 4-OH-TAM and endoxifen isomers. These results suggest that several UGTs may play an important role in the metabolism of endoxifen, that high-prevalence variants in UGTs 1A10, 2B7, 1A8 and 2B15 variants could significantly alter 4-OH-TAM and endoxifen clearance rates in vivo, and that these glucuronidating enzymes could potentially play an important role on overall patient response to TAM.