Superfund Research Program

PCBs and Cytosolic Phenol and Steroid Sulfotransferases

Project Leader: Michael W. Duffel
Grant Number: P42ES013661
Funding Period: 2006-2020

Project-Specific Links

Final Progress Reports

Year:   2019  2014  2009 

The research team’s research advances during 2009 have substantially improved their understanding of the interactions of hydroxylated metabolites of PCBs (i.e. OHPCBs) with mammalian cytosolic sulfotransferases (SULTs). Such interactions of OHPCBs with these enzymes have significance in the interruption of physiological sulfation of many hormones, the metabolism of drugs and other xenobiotics, and the metabolic disposition of the OHPCBs themselves. The team has continued their studies on rat hepatic SULT1A1 (rSULT1A1), a SULT that is well recognized as an important model for family 1 sulfotransferases in both rat and human. In continuing the exploration of the factors that determine interaction of the lower chlorinated OHPCBs with this enzyme, the team’s most recent research efforts have been directed toward the differences that are seen between the oxidized and reduced forms of rSULT1A1 with OHPCBs as inhibitors and substrates. Such oxidative and reductive regulation of sulfotransferase specificity may be highly significant in the context of the effects of oxidative stress on the sulfation of endogenous hormones as well as OHPCBs and other xenobiotics. The research team’s studies on rSULT1A1 indicate that the oxidation-dependent changes in specificity of the enzyme for OHPCBs are most directly related to electronic characteristics of the phenolic hydroxyl (as reflected in calculated pKa values) that derive from the effects of structural differences in OHPCB congeners on the catalytic step of the reaction rather than to initial binding of the OHPCB to the enzyme. In addition to these studies on a family 1 SULT, the team now has evidence that oxidative treatment of a family 2 sulfotransferase, hSULT2A1 (a major human hydroxysteroid sulfotransferase), also changes the catalytic function of that enzyme with dehydroepiandrosterone (DHEA) as substrate. Moreover, these effects are most prominent at low, physiologically relevant, concentrations of DHEA. The team is now currently exploring these effects of redox environment on hSULT2A1 in much more detail, and will also be examining the role of these changes in the interaction of OHPCBs with this enzyme.

Additional research advances during 2009 are providing an enhanced ability to predict the interference of OHPCBs with hSULT2A1-catalyzed sulfation of DHEA. Both substrates and inhibitors of this enzyme could affect the formation of DHEA-sulfate, a major circulating steroid hormone in humans that can serve as a transport form of DHEA from the liver to other tissues. The project team has had initial success in utilizing comparative molecular field analysis to develop a 3-dimensional computational model that correlates steric and electrostatic properties of lower chlorinated OHPCB congeners with their IC50 values for inhibition of the sulfation of DHEA catalyzed by the enzyme. Further studies are underway to explore the extension of this model to more highly chlorinated OHPCBs.