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），人们日益认识到，羟基化衍生物在这些环境污染物的滞留和毒性反应中具有重要作用。OHPCB作为底物和抑制剂与细胞溶质磺基转移酶（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亚型。项目3的长期目标是更好地了解SULT催化功能的调节与半挥发性多氯联苯衍生的OHPCBs生物活性之间的关系。为下一个项目期间提出的工作的主要目标是解决我们在OHPCB与家族2（也称为羟基类固醇或醇）SULT的结构-活性关系方面的知识空白，阐明家族1和家族2 SULT的氧化环境如何调节它们与OHPCB的相互作用。 OHPCBs，并了解在SULT催化反应中形成的OHPCBs的硫酸酯的性质。项目3的中心假设是OHPCB作为家族1和家族2 SULT的底物和抑制剂，并且通过这些酶中硫醇的氧化以可预测的方式显著改变单个OHPCB与这些酶的相互作用。此外，一个推论假设是，硫酸化OHPCB代谢物具有毒理学上重要的化学和生物化学特性。未来5年的研究目标是：1）研究OHPCBs作为人羟类固醇磺基转移酶hSULT 2A 1的抑制剂和底物的构效关系，2）探索SULT中巯基的氧化对OHPCBs作为抑制剂和底物的特异性的调节作用;了解OHPCBs硫酸化产物硫酸酯的性质。这项研究将产生重要的新的基本见解OHPCBs与SULT的相互作用，以及这些相互作用的内源性分子以及外源性物质的硫酸化的潜在后果。

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.