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First published on July 30, 2007; DOI: 10.1124/dmd.107.017145

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Received for publication June 13, 2007.
Revised July 23, 2007.
Accepted for publication July 25, 2007.

Glucuronidation of active tamoxifen metabolites by the human UDP-glucuronosyltransferases (UGTs)

Dongxiao Sun 1, Arun K. Sharma 1, Ryan W. Dellinger 1, Andrea S. Blevins-Primeau 1, Renee Balliet 1, Gang Chen 2, Telih Boyiri 3, Shantu Amin 1, Philip Lazarus 4*

1 Department of Pharmacology, Penn State College of Medicine 2 Department of Health Eveluation Science, Penn State College of Medicine 3 Department of Biochemistry and Molecular Biology, Penn State College of Medicine 4 Penn State University College of Medicine

* Address correspondence to: E-mail: plazarus{at}psu.edu

Abstract

Tamoxifen (TAM) is an anti-estrogen 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-hydroxy (OH)-TAM and 4-OH-N-desmethyl-TAM (endoxifen), is via glucuronidation. While 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 UGTs against isomers of 4-OH-TAM and endoxifen was performed. Using homogenates of individual UGT-overexpressing cell lines, UGTs 2B7 {approx} 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. While 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 {approx} 1A8 > 2B7 exhibited the highest overall glucuronidating activities as determined by Vmax/KM for trans-endoxifen, with the extra-hepatic 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.


Key words: anticancer agents, glucuronidation, HPLC, metabolite kinetics, phase II drug metabolism, UDP glucuronyltransferases


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