Research Project 3
PCBs and Hydroxysteroid (Alcohol) Sulfotransferases
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 Dr. Duffel’s research 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 are to:
1. Address gaps in the knowledge related to structure-activity relationships of OHPCBs with the family 2 (also known as hydroxysteroid or alcohol) SULTs,
2. Elucidate how the oxidative environments of both family 1 and family 2 SULTs regulate their interactions with OHPCBs, and
3. Understand the properties of the sulfuric acid esters of OHPCBs formed in SULT-catalyzed reactions.
Dr. Duffel’s central hypothesis 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 2010-15 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 yields 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.
Project Leader: Michael W. Duffel, PhD
Dr. Duffel is responsible for overall direction of the project, including the planning and design of all experiments, data collection, analysis and interpretation of results, preparation of manuscripts, and progress reports. In addition to experimental design of all phases of Project 3, he will coordinate joint studies with Project 1 of the isrp, and interact directly with both the Synthesis Core and the Analytical Core for preparation of OHPCBs and the analysis of peptide disulfides, respectively.
Co-Project Leader: Larry W. Robertson, PhD, MPH
Dr. Robertson will be directly involved in the design and interpretation of the results of all in vivo studies on the effects of PCBs and OHPCBs in rats. Treatment of rats in Specific Aim 3 of this project will be done jointly with Project 1, and Dr. Robertson and Dr. Duffel will coordinate all aspects of the treatment and acquisition of tissues from rats treated with these agents.
Co-Project Leader: Hans J. Lehmler, PhD
Dr. Lehmler will provide expertise in those portions of the 3D-QSAR studies under Specific Aim 1 that relate to crystal structure- and computationally-based analysis of torsion angles in PCBs and OHPCBs. Although the major portion of Dr. Lehmler's isrp effort is in the Synthesis Core, and that Core will provide synthesis of PCBs and OHPCBs to Project 3, his involvement in guiding conformational analyses of torsion angles of these compounds for Project 3 is additional to his direction of the Synthesis Core.