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Research ArticleArticle

Elimination of Antiestrogenic Effects of Active Tamoxifen Metabolites by Glucuronidation

Yan Zheng, Dongxiao Sun, Arun K. Sharma, Gang Chen, Shantu Amin and Philip Lazarus
Drug Metabolism and Disposition October 2007, 35 (10) 1942-1948; DOI: https://doi.org/10.1124/dmd.107.016279
Yan Zheng
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Dongxiao Sun
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Arun K. Sharma
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Gang Chen
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Shantu Amin
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Philip Lazarus
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Abstract

1-[4-(2-Dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1-(Z)-ene (tamoxifen, TAM) is a nonsteroidal antiestrogen 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-hydroxy-TAM (4-OH-TAM) and endoxifen. Glucuronidation is the major phase II metabolic pathway important in their excretion. Whereas high antiestrogenic 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 antiestrogenic activities of glucuronidated TAM metabolites were determined by examining their effect on the induction of the estrogen-responsive progesterone receptor (PGR) gene. 17β-Estradiol (E2)-mediated PGR gene expression in MCF-7 cells was determined by real-time reverse transcriptase-polymerase chain reaction for each TAM metabolite isomer. E2 (1 × 10-10 M) induction of PGR mRNA was 6-fold after a 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 × 10-6 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 antiestrogenic effects on E2-induced gene expression and that glucuronide conjugates of the same metabolites effectively negate this activity. This result may have important implications in terms of both whole-body and target tissue-specific glucuronidation pathways and individual responses to TAM therapy and cancer prevention.

Footnotes

  • These studies were supported by Public Health Service (PHS) P01-68384 (National Cancer Institute) from the National Institutes of Health, Department of Health and Human Services to P.L. and by a formula grant under the Pennsylvania Department of Health's Health Research Formula Funding Program (State of PA, Act 2001-77, part of the PA Tobacco Settlement Legislation) to P.L.

  • doi:10.1124/dmd.107.016279.

  • ABBREVIATIONS: TAM, tamoxifen, 1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1-(Z)-ene; 4-OH-TAM, 4-hydroxy-TAM; UGT, UDP-glucuronosyltransferase; E2,17β-estradiol; HPLC, high-performance liquid chromatography; TEA, triethylamine; DMSO, dimethyl sulfoxide; DMEM, Dulbecco's modified Eagle medium; PGR, progesterone receptor; UPLC, ultra-performance liquid chromatography; PCR, polymerase chain reaction; RT, reverse transcriptase.

    • Received April 12, 2007.
    • Accepted July 3, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (10)
Drug Metabolism and Disposition
Vol. 35, Issue 10
1 Oct 2007
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Research ArticleArticle

Elimination of Antiestrogenic Effects of Active Tamoxifen Metabolites by Glucuronidation

Yan Zheng, Dongxiao Sun, Arun K. Sharma, Gang Chen, Shantu Amin and Philip Lazarus
Drug Metabolism and Disposition October 1, 2007, 35 (10) 1942-1948; DOI: https://doi.org/10.1124/dmd.107.016279

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Research ArticleArticle

Elimination of Antiestrogenic Effects of Active Tamoxifen Metabolites by Glucuronidation

Yan Zheng, Dongxiao Sun, Arun K. Sharma, Gang Chen, Shantu Amin and Philip Lazarus
Drug Metabolism and Disposition October 1, 2007, 35 (10) 1942-1948; DOI: https://doi.org/10.1124/dmd.107.016279
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