Interactions of the stereoisomers of alpha-hydroxytamoxifen with human hydroxysteroid sulfotransferase SULT2A1 and rat hydroxysteroid sulfotransferase STa

Drug Metabolism and Disposition : the Biological Fate of Chemicals
T Idil Apak, Michael W Duffel

Abstract

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 alpha-hydroxytamoxifen (alpha-OHTAM) and its subsequent sulfation. Alpha-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 alpha-OHTAM with highly purified recombinant STa and SULT2A1. Methods for the preparation of the enantiomers of E- and Z-alpha-OHTAM were developed. When each of the four enantiomers was examined with rat STa, E-(+)-alpha-OHTAM was the only substrate for the enzyme, whereas E-(-)-alpha-OHTAM, Z-(+)-alpha-OHTAM, and Z-(-)-alpha-OHTAM were inhibitors of the sulfation of E-(+)-alpha-OHTAM catalyzed by STa. The dissociation constants for the alpha-OHTAM enantiomers indicated that they bound to STa with similar affinity, but only the E-(+)-enantiomer was a substrate. In contrast to the result...Continue Reading

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