Molecular Toxicology in Human Kidney Cells

人肾细胞的分子毒理学

• 批准号: 7009799
• 负责人: LAWRENCE H. LASH
• 金额: $ 1.36万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009799
• 关键词: Molecular; Toxicology; Human; Kidney; Cells

DESCRIPTION (provided by applicant): A diverse array of environmental and occupational chemicals are nephrotoxicants. It is important to study the interaction of these chemicals because humans are generally exposed to more than one chemical at a time. As a model for these interactions, this proposal will study the effects of two environmental chemicals, trichloroethylene (TRI) and inorganic mercury (Hg), that both have the kidneys as a primary target organ. TRI is carcinogenic in both laboratory animals and in humans while Hg is acutely cytotoxic. Both chemicals also interact with glutathione (GSH). The nephrotoxicity and nephrocarcinogenicity of TRI is attributed to its bioactivation by GSH conjugation and subsequent processing to the penultimate toxic metabolite S-(1 ,2-dichlorovinyl)-L-cysteine (DCVC), which is metabolized by the cysteine conjugate beta-lyase or flavin-containing monooxygenase, to form reactive species. In contrast, the role of GSH in the handling and nephrotoxicity of Hg is more complex, with GSH having both a protective and an intoxifying role. This proposal will study the interactions between TRI, its metabolite DCVC, and Hg in confluent primary cultures of human proximal tubular (hPT) cells and rat PT (rPT) cells under identical incubation conditions. Four hypotheses will be tested: 1) Pre-exposure of hPT and rPT cells to low, subtoxic concentrations of Hg enhances the bioactivation of both TRI and DCVC by enhancement of expression and activity of enzymes involved in TRI and/or DCVC metabolism; 2) pre-exposure of hPT and rPT cells to low, subtoxic concentrations of Hg enhances cytotoxicity of both TRI and DCVC as a consequence of increases in TRI and/or DCVC bioactivation; 3) pre-exposure of hPT and rPT cells to low- to moderately-toxic concentrations of TRI or DCVC enhances Hg-induced cytotoxicity by depletion of GSH; 4) modulation of cytotoxicity of one chemical in hPT and rPT cells by pre-exposure to another chemical is associated with changes in expression of cytokines, growth factors, and/or heat shock proteins. Results from these studies will provide information on the mechanism of interaction of two important environmental toxicants in a model of human and rat kidney cells and will allow us to determine factors that contribute to species differences in susceptibility.

描述（由申请人提供）：各种环境和职业化学物质是肾毒性。研究这些化学物质的相互作用很重要，因为人类通常一次暴露于多种化学物质。作为这些相互作用的模型，该建议将研究两种环境化学物质，三氯乙烯（TRI）和无机汞（HG）的影响，即两者都将肾脏作为主要靶器官。在实验动物和人类中，TRI都是致癌的，而HG急性细胞毒性。两种化学物质也与谷胱甘肽（GSH）相互作用。 TRI的肾毒性和肾癌生成性归因于其通过GSH结合和随后的加工来归因于倒数第二个有毒代谢物S-（1，2-二氯维替尼）-L- cyspsteine（DCVC），这是通过cyabase conjontate conjontate conjontate conjongate conjondate-conjont conjonda单加氧酶，形成反应性物种。相反，GSH在HG的处理和肾毒性中的作用更为复杂，GSH具有保护性和醉酒作用。该建议将研究在相同孵育条件下人类近端管状细胞（HPT）细胞（HPT）细胞（HPT）细胞（HPT）细胞（HPT）细胞的汇合原代培养物中TRI，其代谢产物DCVC和HG之间的相互作用。将测试四个假设：1）HPT和RPT细胞的预曝光量低，hg的低毒性浓度通过增强参与TRI和/或DCVC代谢中涉及的酶的表达和活性来增强TRI和DCVC的生物活化。 2）将HPT和RPT细胞预先暴露至低毒性的HG浓度，从而增强了TRI和DCVC的细胞毒性，这是由于TRI和/或DCVC生物活化的增加而导致的； 3）将HPT和RPT细胞预先暴露至低至中度毒性的TRI或DCVC浓度可通过耗尽GSH增强HG诱导的细胞毒性； 4）通过暴露于另一种化学物质的hpt和RPT细胞中一种化学物质的细胞毒性调节与细胞因子，生长因子和/或热休克蛋白表达的变化有关。这些研究的结果将提供有关人和大鼠肾细胞模型中两种重要环境有毒物质相互作用的机制的信息，并将使我们能够确定导致易感性物种差异的因素。