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Chemoprevention - Experimental/Molecular: Pharmacology, Pharmacogenetics, and Pharmacogenomics

Differences between polymorphic variants of UDP-glucuronosyltransferases (UGTs) active against the major tamoxifen metabolite, endoxifen: Potential impact on individual response of TAM treatment.

College of Medicine, Penn State University, Hershey, PA

Abstract

B99

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. In the present study, characterization of endoxifen glucuronidation by individual UDP-glucuronosyltransferases (UGTs) and relevant UGT polymorphic variants was determined. In vitro assays using human liver microsomes demonstrated that both the trans and cis isomers of endoxifen were catalyzed solely by O-glucuronidation. Of the UGT-over-expressing cell lines tested, the highest overall activity as determined by kinetic analysis (V_max/K_m) were UGTs 1A10>1A8>2B7>1A31A9>1A11A7 for trans-endoxifen, and 1A10>1A9>2B7>1A7>1A8>1A3>1A1 for cis-endoxifen. Although antibodies against UGTs 2B15 and 2B17 were unavailable, both enzymes demonstrated high levels of activity towards cis-endoxifen as determined by K_m analysis. Similar to that observed in liver microsomes, all individual UGTs catalyzed endoxifen-O-glucuronide formation. No detectable activity was observed for UGTs 1A4, 1A6, 2B4, 2B10 and 2B11 against either endoxifen isomer. The UGT1A10^139Lys and UGT2B7^268Tyr variants exhibited significantly (p<0.02) lower glucuronidating activities as determined by in vitro kinetic analysis (V_max/K_m) against endoxifen as compared to their wild type UGT1A10^139Glu and UGT2B7^268His counterparts, an effect observed against both endoxifen isomers. These results suggest that several UGTs may play an important role in the metabolism of endoxifen, that the UGT1A10^139Lys and UGT2B7^268Tyr variants could significantly alter endoxifen clearance rates in vivo, and that UGT variants could potentially play an important role on overall patient response to TAM.