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成羟基衍生物(OHPCbs)，越来越多的人认识到OHPCbs在这些环境污染物的滞留和毒性反应中具有重要作用。OHPCbs作为底物和抑制剂与胞浆中的磺基转移酶(Sults)相互作用，这些相互作用对这些分子毒性的影响取决于OHPCb的结构和所涉及的硫磺的异构体(S)。项目3的长期目标是更好地了解硫磺的催化功能调节与半挥发性多氯联苯的生物活性之间的关系。下一个项目期拟议工作的主要目标是解决我们在有关OHPCB与家族2(也称为羟基类固醇或酒精)结果的结构-活性关系方面的知识空白，以阐明家族1和家族2的氧化环境如何调节它们与 了解在固体催化反应中形成的多氯联苯的硫酸酯的性质。项目3的中心假设是OHPCbs同时作为家族1和家族2结果的底物和抑制剂，并且单个OHPCbs与这些酶的相互作用通过这些酶中的硫醇的氧化以可预测的方式显著改变。此外，一个推论是，硫化的OHPCb代谢物具有重要的毒理化学和生化特性。未来五年要研究的具体目标是：1)研究OHPCbs作为人羟基类固醇磺基转移酶hSULT2A1抑制剂和底物的构效关系；2)探索硫磺中硫醇的氧化在调节其作为抑制剂和底物的专一性中所起的作用；以及3)了解OHPCbs硫酸盐化衍生的硫酸酯的性质。这项研究将对OHPCbs与硫磺的相互作用以及这些相互作用对内源分子和外源物质硫酸盐化的潜在后果产生重要的新的基础性见解。

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.