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化 衍生物(OHPCbs)，这些代谢物在化学致癌、内分泌中发挥重要作用 荷尔蒙紊乱，以及其他毒性反应。有机多氯联苯抑制相关的苯酚转移酶 在甲状腺激素和雌激素的代谢中，但对多氯联苯和雌激素的相互作用知之甚少 OHPCCs与另一个主要的磺基转移酶家族--羟基类固醇(酒精)磺基转移酶， 它们既参与激素代谢，又参与化学致癌。这样做的长期目标是 研究旨在更好地了解多氯联苯和有机多氯联苯对苯系物的催化功能和调节作用 磺基转移酶，并阐明这些作用与多氯联苯和 有机氯联苯对健康有不良影响。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有机多氯联苯对羟基类固醇影响的知识方面的差距 磺基转移酶。这个项目的中心假设是某些多氯联苯和羟基化 多氯联苯的代谢产物可以调节羟基类固醇磺基转移酶的催化功能和/或表达。 这一假说将通过追求三个具体目标来检验：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抑制剂与底物的关系：大鼠 STA和人类SULT2A1；2)探讨氧化还原比变化的影响 谷胱甘肽(多氯联苯代谢产生活性氧物种的结果之一，如在 项目1和项目2)大鼠STA和人SULT2A1以OHPCbs为基础的催化作用 3)研究多氯联苯对大鼠STA表达水平的影响。 和有机多氯联苯。这项研究将对半挥发性多氯联苯和 有机多氯联苯对类固醇激素中重要的羟基类固醇磺基转移酶有调节作用 致癌的羟烷基多环芳烃的动态平衡和代谢活化 碳氢化合物。

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.