HEAT SHOCK IN TOXICITY ASSAYS

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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.