The potent inhibition of human cytosolic sulfotransferase 1A1 by 17α-ethinylestradiol is due to interactions with isoleucine 89 on loop 1

Katie Jo Rohn-Glowacki; Charles N. Falany

doi:10.1515/hmbci-2014-0028

Article

The potent inhibition of human cytosolic sulfotransferase 1A1 by 17α-ethinylestradiol is due to interactions with isoleucine 89 on loop 1

Katie Jo Rohn-Glowacki and Charles N. Falany

Published/Copyright: November 22, 2014

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From the journal Hormone Molecular Biology and Clinical Investigation Volume 20 Issue 3

Abstract

Drug-drug interactions (DDI) with oral contraceptives containing 17α-ethinylestradiol (EE2) have been well characterized with regard to interactions with phase I drug metaolizing enzymes; however, DDI with EE2 and phase II enzymes have not been as thoroughly addressed. Our laboratory recently reported that in vitro EE2 potently inhibits human cytosolic sulfotransferase (SULT) 1A1 while EE2 was not sulfated until micromolar concentrations. Molecular docking studies demonstrated that Tyr169 and isoleucine 89 (Ile89) may play a role in the inhibitory and/or catalytic positioning of EE2 within the active site of SULT1A1. Therefore, the current study focused on determining the role of Ile89 in the inhibition of SULT1A1 utilizing site-directed mutagenesis. Ile89 was mutated to an alanine and the effect of the mutation was characterized using kinetic and binding assays. SULT1A1-Ile89Ala was found to have a Km for EE2 that was 11-fold greater than wild-type enzyme. A decreased affinity (Kd) of EE2 for SULT1A1-Ile89Ala was apparently responsible for the increase in Km, and also resulted in the loss of the potent inhibition. Molecular modeling was used in an attempt to determine the atomic level changes in binding of EE2 to SULT1A1-Ile89Ala. However, analysis of the effect of the single Ile89 mutation on both the open and closed homology models was not consistent with the docking and kinetic results. Overall, the mechanism of inhibition of EE2 for SULT1A1 is apparently the result of interactions of Ile89 with EE2 holding it in a potent inhibitory conformation, and mutation of the Ile89 significantly decreases the inhibition.

Keywords: 17α-ethinylestradiol; birth control; oral contraceptives; sulfotransferase (SULT)

Corresponding author: Charles N. Falany, PhD, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall 151, Birmingham, AL 35294, USA, Phone: 205-934-9848, Fax: 205-934-8240, E-mail: cfalany@uab.edu

Acknowledgments

This work was funded by the National Institute of Health Grant GM38953. The authors have no conflict of interest to report.

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Received: 2014-9-23

Accepted: 2014-10-20

Published Online: 2014-11-22

Published in Print: 2014-12-1

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Articles in the same Issue

https://doi.org/10.1515/hmbci-2014-0028

Keywords for this article

17α-ethinylestradiol; birth control; oral contraceptives; sulfotransferase (SULT)