Polychlorinated biphenyls (PCBs) are metabolized in humans and other mammals to hydroxylated derivatives (OHPCBs) that are increasingly recognized as having significant roles in the retention of, and toxic responses to, these environmental contaminants. OHPCBs interact with cytosolic sulfotransferases (SULTs) as substrates and inhibitors, and the effects of these interactions on the toxicities of these molecules depend upon the structure of the OHPCB and the isoform(s) of SULT involved. The long term goal of Project 3 is to better understand relationships between the regulation of catalytic function of SULTs and the biological activities of OHPCBs derived from semi-volatile PCBs. The primary objectives of the work proposed for the next project period are to address gaps in our knowledge related to structure-activity relationships of OHPCBs with the family 2 (also known as hydroxysteroid or alcohol) SULTs, to elucidate how the oxidative environments of both family 1 and family 2 SULTs regulate their interactions with OHPCBs, and to understand the properties of the sulfuric acid esters of OHPCBs formed in SULT-catalyzed reactions. The central hypothesis for Project 3 is that OHPCBs serve as substrates and inhibitors of both family 1 and family 2 SULTs, and that the interactions of individual OHPCBs with these enzymes are significantly altered in a predictable manner by oxidation of thiols in these enzymes. Moreover, a corollary hypothesis is that the sulfated OHPCB-metabolites have toxicologically important chemical and biochemical properties.
The specific aims to be investigated during the next five-year period are: 1) to study the structure-activity relationships for OHPCBs as inhibitors and substrates of human hydroxysteroid sulfotransferase hSULT2A1;2) to explore the roles that the oxidation of thiols in SULTs play in regulation of their specificity for OHPCBs as inhibitors and substrates;and 3) to understand the properties of the sulfuric acid esters derived from sulfation of OHPCBs. This research will yield significant new fundamental insight into the interactions of OHPCBs with SULTs, and the potential consequences of these interactions for sulfation of endogenous molecules as well as xenobiotics.
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