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Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase hSULT2A1
Author(s) -
Squirewell Edwin,
Qin Xiaoyan,
Duffel Michael W.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.892.9
Subject(s) - sulfation , tamoxifen , dehydroepiandrosterone , chemistry , sulfotransferase , enzyme , steroid , metabolite , pharmacology , substrate (aquarium) , hormone , cancer , medicine , endocrinology , biochemistry , breast cancer , androgen , biology , ecology
Tamoxifen is a breast cancer therapeutic that has been shown to cause endometrial cancer in some women following treatment. hSULT2A1 is an enzyme that catalyzes the formation of an α‐sulfooxy derivative of tamoxifen that is reactive towards DNA. Moreover, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenenolone (PREG). We hypothesize that major metabolites of tamoxifen regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. Our studies show that endoxifen is a potent inhibitor of hSULT2A1‐catalyzed sulfation of PREG and DHEA with Ki values of 3.5 μM and 2.8 μM, respectively. 4‐Hydroxytamoxifen and N ‐desmethyltamoxifen had Ki values of 12.7 μM and 9.8 μM, respectively, for sulfation of PREG, whereas Ki values of 19.4 μM and 17.2 μM were observed for these metabolites when determining the sulfation of DHEA. A Ki of 9.1 μM was observed for tamoxifen‐ N ‐oxide when DHEA was used as a substrate, and this increased to a Ki value of 16.9 μM when PREG was utilized as a substrate. Subsequent assays indicated that N ‐desmethyltamoxifen was a substrate for the enzyme. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules. [Supported by NIH grant CA038683]