%0 Journal Article %A T. Idil Apak %A Michael W. Duffel %T INTERACTIONS OF THE STEREOISOMERS OF α-HYDROXYTAMOXIFEN WITH HUMAN HYDROXYSTEROID SULFOTRANSFERASE SULT2A1 AND RAT HYDROXYSTEROID SULFOTRANSFERASE STA %D 2004 %R 10.1124/dmd.104.000919 %J Drug Metabolism and Disposition %P 1501-1508 %V 32 %N 12 %X Tamoxifen (TAM) is a nonsteroidal antiestrogenic drug that is widely used for the treatment of estrogen receptor-dependent breast cancer. An increased risk of endometrial cancer in some patients treated with TAM has been linked to the metabolic formation of α-hydroxytamoxifen (α-OHTAM) and its subsequent sulfation. α-OHTAM has been found to be a substrate for rat and human hydroxysteroid sulfotransferases (STa and SULT2A1, respectively). Since stereochemistry plays an important role in the interactions of hydroxysteroid sulfotransferases with their substrates, we have now investigated the interactions of each of the stereoisomers of α-OHTAM with highly purified recombinant STa and SULT2A1. Methods for the preparation of the enantiomers of E- and Z-α-OHTAM were developed. When each of the four enantiomers was examined with rat STa, E-(+)-α-OHTAM was the only substrate for the enzyme, whereas E-(-)-α-OHTAM, Z-(+)-α-OHTAM, and Z-(-)-α-OHTAM were inhibitors of the sulfation of E-(+)-α-OHTAM catalyzed by STa. The dissociation constants for the α-OHTAM enantiomers indicated that they bound to STa with similar affinity, but only the E-(+)-enantiomer was a substrate. In contrast to the results obtained with rat hydroxysteroid sulfotransferase STa, all enantiomers of α-OHTAM were substrates for the human SULT2A1. Moreover, kcat/Km values with SULT2A1 were higher with the Z enantiomers than with the E enantiomers. As a result of the potential for interconversion of the E and Z geometric isomers upon metabolism, the sulfation of the Z isomers may be of greater concern in human tissues than has been previously assumed. The American Society for Pharmacology and Experimental Therapeutics %U https://dmd.aspetjournals.org/content/dmd/32/12/1501.full.pdf