HEAT SHOCK IN TOXICITY ASSAYS

热休克蛋白(HSP)或应激蛋白基因表达 通过一系列令人紧张的化学物质和治疗方法来增强 传给细胞。通常，用诱导HSP的试剂进行预处理 合成使细胞对随后的挑战具有抵抗力 或其他代理人在否则会导致死亡的条件下。这个 基因无处不在，并编码少量相对较高的 保守的蛋白质。已知有几种热休克蛋白可以与其他蛋白质结合， 其中一些(包括70,000个道尔顿或HSP70蛋白)具有 偏好未折叠的多肽，并作为分子发挥作用 伴侣，促进重要的细胞过程，如蛋白质 合成和贩卖。热休克蛋白基因转录的调控 由HSP基因特异性转录因子HSF介导，其活性 似乎受未参与的HSP70浓度的调节。因为 在它们的调控中，热休克蛋白被认为是可能的分子- 毒性的生物标志物。根据它们的性质，我们 假设热休克蛋白，特别是热休克蛋白70类的热休克蛋白也可能是 与许多复杂的分子作用机制有关 毒药。这项建议是用鼠标来刻画 肝毒性模型，热休克蛋白基因表达对暴露的反应 有机体对具有良好特性的毒物，并检验以下假设 热休克蛋白保护肝细胞免受许多毒物的损害，因此它们可能 通过相互作用参与许多毒物的作用机制， 直接或间接地，与这些产生的加合蛋白 生物转化后的毒物与热休克蛋白基因上调 表达反映细胞对毒物的反应，起到提供 额外的热休克蛋白“中和”加合物的蛋白质。

Expression of heat shock protein (hsp) or stress protein genes is enhanced by a diverse set of chemicals and treatments that are stressful to cells. Frequently, pretreatment with an agent that induces hsp synthesis renders cells resistant to subsequent challenges with the same or other agents under conditions that would otherwise cause death. The genes are ubiquitous and encode a small number of relatively highly conserved proteins. Several hsps are known to bind to other proteins, some of them (including the 70,000 dalton or hsp70 proteins) having a preference for unfolded polypeptides, and to function as molecular chaperones, facilitating important cellular processes such as protein synthesis and trafficking. Regulation of transcription of hsp genes is mediated by hsp gene-specific transcription factor HSF whose activity appears to be regulated by the concentration of unengaged hsp70. Because of their regulation, hsps are being discussed as possible molecular- biological markers for toxicity. Based on their properties we hypothesize that hsps, especially those of the hsp70 class, may also be intricately related to the molecular mechanisms of action of many toxicants. This proposal is to characterize, using a mouse hepatotoxicity model, hsp gene expression in response to exposure of the organism to well-characterized toxicants, and to test the hypotheses that hsps protect hepatic cells from damage by many toxicants, that they may participate in the mechanisms of action of many toxicants by interacting, directly or indirectly, with adducted proteins produced by these toxicants following bioconversion, and that upregulation of hsp gene expression reflects the cell's response to toxicants, serving to provide extra hsps to "neutralize" adducted proteins.