BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

环境化学品对人类和其他人具有多效性毒性作用 包括器官衰竭、出生缺陷和癌症在内的生物体 由复杂的分子和生化信号模式引发。vt.给出 数以千计的环境毒素，很难确定 作用机制或识别这些反应的致病因素。 然而，很明显，生物后果是由于 毒素或代谢物与细胞成分的相互作用。 尽管细胞中有许多毒素的靶标，但对许多 不同的靶标可能会引发共同的毒性生化机制， 例如，钙离子稳态改变，谷胱甘肽耗竭和氧化 压力，将损害与细胞死亡联系在一起。因此，多效性 对化学毒素的反应可能与较少数量的 生化事件。 基因表达的变化是对环境毒素的常见反应， 并可用于调节导致多形性的早期事件 生物反应。最常见的基因被激活 化学毒素是应激反应基因，如热休克蛋白， 葡萄糖调节蛋白和转录激活因子。它是 这些分子应激反应可能参与了 毒性的发展，或保护。我们的长期目标是 确定应激基因表达的变化是否代表 对毒素的生物反应的调节。具体的假设 要测试的是，“压力表达增加的信号 应答基因与介导细胞毒性的信号重叠 不同类别的化学毒素。我们将使用一种具有良好特性的 毒性的细胞模型，LLC-PK1细胞，和三种不同的毒素， 碘乙酰胺，叔丁基氢过氧化氢和肾毒性半胱氨酸结合物， 来检验这一假设。3应激反应的激活机制 这三种毒素的基因(hsp70、grp78和gadd153)将与 确定共同转录和转录后信号转导 机制是存在的。我们还将开始研究以确定基因组 对毒素抵抗力不同的基础。我们的希望是 阐明这些基本的分子反应将使我们能够更好地 了解导致生物反应的一连串事件 化学毒素。

Environmental chemicals have pleotropic toxic effects on humans and other organisms including organ failure, birth defects and cancers, which are elicited by a complex pattern of molecular and biochemical signals. Given the thousands of environmental toxins, it can be difficult to determine a mechanism of action or to identify -causative agents for these responses. However, it is clear that the biological consequences are due to the interaction of the toxin, or a metabolite, with components of the cell. Although there are many targets for toxins in a cell, damage to many different targets may elicit common biochemical mechanisms of toxicity, e.g. altered Ca2+ homeostasis, depletion of glutathione and oxidative stress, which couple the damage to cell death. Therefore, the pleotropic responses to chemical toxins may be linked by a smaller number of biochemical events. A change in gene expression is a common response to environmental toxins, and may serve to regulate early events which lead to the pleotropic biological responses. The most common genes which are activated by chemical toxins are stress response genes such as heat shock proteins, glucose regulated proteins and transcription activating factors. It is possible that these molecular stress responses are involved either in development of toxicities, or protection. Our long term goal is to determine if changes in stress gene expression represent common points of regulation for the biological response to,toxins. The specific hypothesis to be tested is, "The signals for increased expression of stress responsive genes overlap with the signals which mediate cytotoxicity for different classes of chemical toxins." We will use a well characterized cell model of toxicity, LLC-PK1 cells, and three different toxins, iodoacetamide, t-butylhydroperoxide and nephrotoxic cysteine conjugates, to test this hypothesis. Mechanisms for activation of 3 stress responsive genes (hsp7O, grp78 and gadd153) by all three toxins will be compared to determine if common transcriptional and posttranscriptional signalling mechanisms exist. We will also begin studies to determine the genomic basis for differences in resistance to toxins. Our hope is that elucidating these fundamental molecular responses will allow us to better understand the cascade of events which result in the biological response to chemical toxins.