Journal article
The effects of endoxifen and other major metabolites of tamoxifen on the sulfation of estradiol catalyzed by human cytosolic sulfotransferases hSULT1E1 and hSULT1A11
Drug metabolism and disposition, Vol.43(6), pp.843-850
06/2015
DOI: 10.1124/dmd.115.063206
PMCID: PMC4429681
PMID: 25819444
Abstract
Tamoxifen is successfully used for both treatment and prevention of estrogen-dependent breast cancer, yet side effects and development of resistance remain problematic. Endoxifen is a major active metabolite of tamoxifen that is being investigated for clinical use. We hypothesized that endoxifen and perhaps other major metabolites of tamoxifen may affect the ability of human estrogen sulfotransferase 1E1 (hSULT1E1) and human phenol sulfotransferase 1A1 isoform 1 (hSULT1A1*1) to catalyze the sulfation of estradiol, an important mechanism in termination of estrogen signaling through loss of activity at estrogen receptors. Our results indicated that endoxifen, N-desmethyltamoxifen (N-desTAM), 4-hydroxytamoxifen (4-OHTAM), and tamoxifen-N-oxide were weak inhibitors of hSULT1E1 with Ki values ranging from 10 μM to 38 μM (i.e., over 1000 times higher than the 8.1 nM Km value for estradiol as substrate for the enzyme). In contrast to the results with hSULT1E1, endoxifen and 4-OHTAM were significant inhibitors of the sulfation of 2.0 µM estradiol catalyzed by hSULT1A1*1, with IC50 values (9.9 μM and 1.6 μM, respectively) that were similar to the Km value (1.5 μM) for estradiol as substrate for this enzyme. Additional investigation of the interaction of these metabolites with the two sulfotransferases revealed that endoxifen, 4-OHTAM, and N-desTAM were substrates for hSULT1E1 and hSULT1A1*1, although the relative catalytic efficiencies varied with both the substrate and the enzyme. These results may assist in future elucidation of cell- and tissue-specific effects of tamoxifen and its metabolites.
Details
- Title: Subtitle
- The effects of endoxifen and other major metabolites of tamoxifen on the sulfation of estradiol catalyzed by human cytosolic sulfotransferases hSULT1E1 and hSULT1A11
- Creators
- Edwin J Squirewell - Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, IowaMichael W Duffel - Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa michael-duffel@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Drug metabolism and disposition, Vol.43(6), pp.843-850
- Publisher
- United States
- DOI
- 10.1124/dmd.115.063206
- PMID
- 25819444
- PMCID
- PMC4429681
- ISSN
- 0090-9556
- eISSN
- 1521-009X
- Grant note
- R01 CA038683 / NCI NIH HHS
- Language
- English
- Date published
- 06/2015
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984065698202771
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