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Drug Metabolism and Disposition Fast Forward
First published on July 9, 2007; DOI: 10.1124/dmd.107.016279

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Received for publication April 13, 2007.
Revised July 2, 2007.
Accepted for publication July 3, 2007.

ELIMINATION OF ANTI-ESTROGENIC EFFECTS OF ACTIVE TAMOXIFEN METABOLITES BY GLUCURONIDATION

Yan Zheng 1, Dongxiao Sun 1, Arun k Sharma 1, Gang Chen 1, Shantu Amin 1, Philip Lazarus 1*

1 Penn State University College of Medicine

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

Abstract

TAM is a nonsteroidal anti-estrogen that has been commonly used for the prevention and treatment of estrogen receptor-positive breast cancer. TAM is extensively metabolized into several primary active metabolites including 4-OH-TAM and endoxifen. Glucuronidation is the major phase II metabolic pathway important in their excretion. While high anti-estrogenic activity has been reported for both 4-OH-TAM and endoxifen, studies examining the effect of glucuronide conjugation of these metabolites have not previously been performed. In the present study, the anti-estrogenic activities of glucuronidated TAM metabolites were determined by examining their effect on the induction of the estrogen-responsive PGR gene. E2-mediated PGR gene expression in MCF-7 cells was determined by real-time RT-PCR for each TAM metabolite isomer. E2 (1x10-10 M) induction of PGR mRNA was 6-fold after 12 h incubation; only unconjugated TAM metabolites inhibited this effect. A virtually identical dose-dependent inhibition of E2-induced PGR gene expression was found for both the trans and cis isomers of 4-OH-TAM and endoxifen, with maximal inhibition attained at 1 x10-6 M of TAM metabolite. The glucuronide conjugates of all 4-OH-TAM and endoxifen isomers exhibited no effect on E2-mediated induction of PGR expression at all concentrations of TAM metabolite examined in this study. These data indicate that isomers of both 4-OH-TAM and endoxifen exhibit roughly equipotent anti-estrogenic effects on E2-induced gene expression and that glucuronide conjugates of the same metabolites effectively negate this activity. This may has important implications in terms of both whole-body and target-tissue-specific glucuronidation pathways and individual response to TAM therapy and cancer prevention.


Key words: drug disposition, glucuronidation, phase II drug metabolism, UDP glucuronyltransferases




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