Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1).
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Squirewell EJ, Qin X, Duffel MW
Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1).
Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25.
- PubMed ID
- 25157097 [ View in PubMed]
- Abstract
Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an alpha-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with Ki values of 3.5 and 2.8 muM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited Ki values of 12.7 and 9.8 muM, respectively, whereas corresponding Ki values of 19.4 and 17.2 muM were observed with DHEA as substrate. A Ki value of 9.1 muM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 muM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Tamoxifen Bile salt sulfotransferase Protein Humans UnknownSubstrateDetails Tamoxifen Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails - Drug Reactions
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