Journal article
Elimination of antiestrogenic effects of active tamoxifen metabolites by glucuronidation
Drug metabolism and disposition, Vol.35(10), pp.1942-1948
2007
Handle:
https://hdl.handle.net/2376/113550
PMID: 17620345
Abstract
1-[4-(2-Dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1-(Z)-ene (ta-isomer. E 2 (1 10 10 M) induction of PGR mRNA was 6-fold after a moxifen, TAM) is a nonsteroidal antiestrogen that has been com-12-h incubation; only unconjugated TAM metabolites inhibited this monly used for the prevention and treatment of estrogen receptor-effect. A virtually identical dose-dependent inhibition of E 2-induced positive breast cancer. TAM is extensively metabolized into several PGR gene expression was found for both the trans-and cis-isomers primary active metabolites including 4-hydroxy-TAM (4-OH-TAM) and of 4-OH-TAM and endoxifen, with maximal inhibition attained at 1 endoxifen. Glucuronidation is the major phase II metabolic pathway 10 6 M of TAM metabolite. The glucuronide conjugates of all 4-OH-important in their excretion. Whereas high antiestrogenic activity has TAM and endoxifen isomers exhibited no effect on E 2-mediated in-been reported for both 4-OH-TAM and endoxifen, studies examining duction of PGR expression at all concentrations of TAM metabolite the effect of glucuronide conjugation of these metabolites have not examined in this study. These data indicate that isomers of both previously been performed. In the present study, the antiestrogenic 4-OH-TAM and endoxifen exhibit roughly equipotent antiestrogenic activities of glucuronidated TAM metabolites were determined by effects on E 2-induced gene expression and that glucuronide conju-examining their effect on the induction of the estrogen-responsive gates of the same metabolites effectively negate this activity. This progesterone receptor (PGR) gene. 17-Estradiol (E 2)-mediated PGR result may have important implications in terms of both whole-body gene expression in MCF-7 cells was determined by real-time reverse and target tissue-specific glucuronidation pathways and individual transcriptase-polymerase chain reaction for each TAM metabolite responses to TAM therapy and cancer prevention.
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Details
- Title
- Elimination of antiestrogenic effects of active tamoxifen metabolites by glucuronidation
- Creators
- YAN ZHENG - Cancer Prevention and Control, Penn State Cancer Institute, Hershey, Pennsylvania, United StatesDONGXIAO SUN - Cancer Prevention and Control, Penn State Cancer Institute, Hershey, Pennsylvania, United StatesArun K SHARMA - Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United StatesGang Chen - Cancer Prevention and Control, Penn State Cancer Institute, Hershey, Pennsylvania, United StatesShantu AMIN - Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United StatesPhilip LAZARUS - Cancer Prevention and Control, Penn State Cancer Institute, Hershey, Pennsylvania, United States
- Publication Details
- Drug metabolism and disposition, Vol.35(10), pp.1942-1948
- Academic Unit
- Department of Pharmaceutical Sciences
- Publisher
- American Society for Pharmacology and Experimental Therapeutics; Bethesda, MD
- Number of pages
- 7
- Identifiers
- 99900547966101842
- Language
- English
- Resource Type
- Journal article