title: Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1.
abstract: Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and exposure to PCBs and their hydroxylated metabolites (OHPCBs) has been associated with various adverse health effects. The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of OHPCBs, and the interaction of OHPCBs with both the SULT1 and SULT2 families of these enzymes has received attention both with respect to metabolic disposition of these molecules and the potential mechanisms for their roles in endocrine disruption. We have previously shown that OHPCBs interact with human hydroxysteroid sulfotransferase hSULT2A1, an enzyme that catalyzes the sulfation of dehydroepiandrosterone (DHEA), other alcohol-containing steroids, bile acids, and many xenobiotics. The objective of our current studies is to investigate the mechanism of inhibition of hSULT2A1 by OHPCBs by combining inhibition kinetics with determination of equilibrium binding constants and molecular modeling of potential interactions. Examination of the effects of fifteen OHPCBs on the sulfation of DHEA catalyzed by hSULT2A1 showed predominantly noncompetitive inhibition patterns. This was observed for OHPCBs that were substrates for sulfation reactions catalyzed by the enzyme as well as those that solely inhibited the sulfation of DHEA. Equilibrium binding experiments and molecular modeling studies indicated that the OHPCBs bind at the binding site for DHEA on the enzyme, and that the observed noncompetitive patterns of inhibition are consistent with binding in more than one orientation to more than one enzyme complex. These results have implications for the roles of SULTs in the toxicology of OHPCBs, while also providing molecular probes of the complexity of substrate/inhibitor interactions with hSULT2A1.
authors: Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States.
authors: Edugie J
authors: EJ
authors: Ekuase
authors: Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, United States.
authors: Hans-Joachim
authors: HJ
authors: Lehmler
authors: Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, United States.
authors: Larry W
authors: LW
authors: Robertson
authors: Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States. Electronic address: michael-duffel@uiowa.edu.
authors: Michael W
authors: MW
authors: Duffel
mesh_terms: D000818:Animals; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004785:Environmental Pollutants / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D008958:Models, Molecular; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D003687:Dehydroepiandrosterone; D011078:Polychlorinated Biphenyls; D015238:Sulfotransferases; C028152:alcohol sulfotransferase
keywords: Hydroxylated polychlorinated biphenyl; OHPCB; PCB; Sulfotransferase; hSULT2A1