Glutathione conjugation of environmental toxins

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The vacinal haloalkenes are toxicants commonly found at many Superfund sites. Of the 30 most common toxicants detected at Superfund sites, five are nephrotoxic vacinal haloalkenes. Unlike other halogenated hydrocarbons, vacinal haloalkenes uniquely damage the kidney by destroying proximal tubules cells and induce renal carcinomas. It is believed the nephrotoxic and nephrocarcinogenic effects of vicinal haloalkenes stems from their conversion by hepatic microsomal glutathione transferase to GSH-conjugates which are converted in their intestine to cysteine-S-conjugates, which are then cleaved by renal cysteine beta-lyases to form toxic haloalkylthiols. The production of these haloalkylthiols is ultimately responsible for destruction of renal proximal tubular cells. Confirmation of this hypothesis has been difficult due to the complex interaction between three organ systems and lack of in vitro models. Complicating the issue is the recent discovery there exists more than one microsomal glutathione transferase. Our objectives are: [1] to definitively determine the role of individual MGSTs in modulating hepatotoxicity & nephrotoxicity of the Superfund vacinal haloalkene contaminates. This will be accomplished by isolating the three different MGST genes and producing "knockout" or over-expressing transgenic animals. The sensitivity of these animals to the vacinal haloalkenes detected at Superfund sites will then be determined. [2] to comprehensively identify genes whose expression is dramatically altered upon exposure to low levels of these vacinal haloalkenes This will be accomplished through the use of cDNA microarray technology. [3] to use this information to develop novel biomarkers and animal models capable of detecting subtle halogenated & aromatic hydrocarbon damage not detectable by existing histopathological or biochemical techniques. Current models only detect damage arising from frank tissue damage and repair, or subsequent development of tumors, which normally require exposure to high doses. The models developed in this project, in contrast, should be able to detect alteration in cellular homeostasis arising from exposure to low-levels of the vacinal haloalkenes and any other toxin capable of producing liver or renal damage.