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的 这些代谢产物在化学致癌作用、内分泌代谢、 激素紊乱和其他毒性反应。OHPCBs抑制苯酚磺基转移酶， 在甲状腺激素和雌激素的代谢，但很少有人知道的多氯联苯和 OHPCB与另一个主要的磺基转移酶家族，羟基类固醇（醇）磺基转移酶， 它们参与激素代谢和化学致癌作用。长期目标是 研究是为了更好地了解多氯联苯和OHPCBs对催化功能和调节的影响， 磺基转移酶，并阐明这些影响和多氯联苯的作用， OHPCBs对健康有不利影响。本项目拟议工作的主要目标 是为了解决我们在多氯联苯和OHPCBs对羟基类固醇的影响方面的知识差距差距。 磺基转移酶该项目的中心假设是，某些多氯联苯和羟基化 多氯联苯代谢物可以调节羟基类固醇磺基转移酶的催化功能和/或表达。 这一假设将通过追求三个具体目标进行检验：1）研究30-定量结构-活性 OHPCBs作为两种模型羟基类固醇磺基转移酶的抑制剂和底物的关系：大鼠 STa和人SULT 2A 1; 2）探索氧化与还原的比率变化对STa和人SULT 2A 1的影响。 谷胱甘肽（研究中发现， 项目1和项目2）对大鼠STa和人SULT 2A 1与OHPCBs作为 底物和抑制剂; 3）研究PCBs介导的大鼠STa表达水平的变化 和OPCBs。这项研究将产生重要的新见解的影响，半挥发性多氯联苯和 OHPCBs在调节类固醇激素中重要的羟基类固醇磺基转移酶中具有重要作用 体内平衡以及致癌羟烷基多环芳烃的代谢活化 芳香烃.

Polychlorinated biphenyls (PCBs) are metabolized in humans and other mammals to hydroxylated derivatives (OHPCBs), and these metabolites play significant roles in chemical carcinogenesis, endocrine hormone disruption, and other toxic responses. OHPCBs inhibit phenol sulfotransferases that are involved in the metabolism of thyroid hormone and estrogens, but little is known about the interactions of PCBs and OHPCBs with another major family of sulfotransferases, the hydroxysteroid (alcohol) sulfotransferases, which are involved both in hormone metabolism and chemical carcinogenesis. The long term goal of this research is to better understand the effects of PCBs and OHPCBs on the catalytic function and regulation of sulfotransferases and to elucidate the relationships between these effects and the roles that PCBs and OHPCBs have in adverse health effects. The primary objective of the work proposed for the present project is to address the gap in our knowledge related to the effects of PCBs and OHPCBs on the hydroxysteroid sulfotransferases. The central hypothesis for this project is that certain PCBs and hydroxylated metabolites of PCBs can regulate catalytic function and/or expression of hydroxysteroid sulfotransferases. This hypothesis will be tested by pursuing three specific aims: 1) to study 30-quantitative structure-activity relationships for OHPCBs as inhibitors and substrates of two model hydroxysteroid sulfotransferases: rat STa and human SULT2A1; 2) to explore the effects of changes in the ratio of oxidized to reduced glutathione (one result of the generation of reactive oxygen species from PCB-metabolism as studied in Project 1 and Project 2) on the catalytic function of rat STa and human SULT2A1 with OHPCBs as substrates and inhibitors; and 3) to study changes in the levels of expression of rat STa mediated by PCBs and OHPCBs. This research will yield significant new insight into the effects that semi-volatile PCBs and OHPCBs have in regulating hydroxysteroid sulfotransferases that are important in steroid hormone homeostasis as well as in the metabolic activation of carcinogenic hydroxyalkyl polycyclic aromatic hydrocarbons.