Project 3: PCBs and Hydroxysteroid (Alcohol) Sulfotransferases

多氯联苯（PCBs）在人类和其他哺乳动物体内代谢为羟基化衍生物（OHPCBs），羟基化衍生物在这些环境污染物的保留和毒性反应中发挥着重要作用。OHPCB作为底物和抑制剂与细胞质硫转移酶（SULT）相互作用，这些相互作用对这些分子毒性的影响取决于OHPCB的结构和所涉及的SULT的异构体。项目3的长期目标是更好地了解SULTs的催化功能调节与半挥发性多氯联苯衍生的ohpcb生物活性之间的关系。下一个项目期间提出的工作的主要目标是解决OHPCBs与家族2（也称为羟基类固醇或酒精）SULTs的结构-活性关系方面的知识空白，阐明家族1和家族2 SULTs的氧化环境如何调节它们与

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.