PT  - JOURNAL ARTICLE
AU  - Dongxiao Sun
AU  - Arun K. Sharma
AU  - Ryan W. Dellinger
AU  - Andrea S. Blevins-Primeau
AU  - Renee M. Balliet
AU  - Gang Chen
AU  - Telih Boyiri
AU  - Shantu Amin
AU  - Philip Lazarus
TI  - Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases
AID  - 10.1124/dmd.107.017145
DP  - 2007 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 2006--2014
VI  - 35
IP  - 11
4099  - http://dmd.aspetjournals.org/content/35/11/2006.short
4100  - http://dmd.aspetjournals.org/content/35/11/2006.full
SO  - Drug Metab Dispos2007 Nov 01; 35
AB  - Tamoxifen (TAM) is an antiestrogen that has been widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism and elimination of TAM and its major active metabolites 4-hydroxytamoxifen (4-OH-TAM) and 4-OH-N-desmethyl-TAM (endoxifen; 4-hydroxy-N-desmethyl-tamoxifen) is via glucuronidation. Although limited studies have been performed characterizing the glucuronidation of 4-OH-TAM, no studies have been performed on endoxifen. In the present study, characterization of the glucuronidating activities of human UDP glucuronosyltransferases (UGTs) against isomers of 4-OH-TAM and endoxifen was performed. Using homogenates of individual UGT-overexpressing cell lines, UGTs 2B7 ∼ 1A8 > UGT1A10 exhibited the highest overall O-glucuronidating activity against trans-4-OH-TAM as determined by Vmax/KM, with the hepatic enzyme UGT2B7 exhibiting the highest binding affinity and lowest KM (3.7 μM). As determined by Vmax/KM, UGT1A10 exhibited the highest overall O-glucuronidating activity against cis-4-OH-TAM, 10-fold higher than the next-most active UGTs 1A1 and 2B7, but with UGT1A7 exhibiting the lowest KM. Although both N- and O-glucuronidation occurred for 4-OH-TAM in human liver microsomes, only O-glucuronidating activity was observed for endoxifen; no endoxifen-N-glucuronidation was observed for any UGT tested. UGTs 1A10 ∼ 1A8 > UGT2B7 exhibited the highest overall glucuronidating activities as determined by Vmax/KM for trans-endoxifen, with the extrahepatic enzyme UGT1A10 exhibiting the highest binding affinity and lowest KM (39.9 μM). Similar to that observed for cis-4-OH-TAM, UGT1A10 also exhibited the highest activity for cis-endoxifen. These data suggest that several UGTs, including UGTs 1A10, 2B7, and 1A8 play an important role in the metabolism of 4-OH-TAM and endoxifen. The American Society for Pharmacology and Experimental Therapeutics