ALDO-KETO REDUCTASES AS PART OF CHEMICAL STRESS RESPONSE

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DESCRIPTION: Aldo-keto reductases provide protection against environmental and nutritional toxins and carcinogens by detoxification of reactive aldehydes capable of modifying cellular macromolecules. Chemical stress induces the expression of a number of detoxification enzymes. Thus, aflatoxin reductase is induced by ethoxyquin and other antioxidants. Recently it was shown that ethoxyquin and antiobiotic tunicamycin also induce aldehyde reductase, another member of the aldo-keto reductase family. A crucial element of the human aldehyde reductase gene promoter binds transcription factor CHOP, which is induced in cells exposed to chemical stress. Preliminary results suggest that CHOP mediates the induction of aldehyde reductase expression and that both aflatoxin and aldehyde reductases are part of the cellular chemical stress response system, hence their expression is induced in response to toxic insult. The application proposes to: a) evaluate the ability of physiologically relevant compounds to induce aldehyde reductase expression and to find out whether induction of both reductases goes through the CHOP-dependent pathway. B) test the compounds of the two major groups: toxic substrates and chemoprotectors that are known to induce aflatoxin reductase and other drug metabolizing enzymes (e.g. glutathione-S-transferase). C) test the Selected stimuli for their ability to induce CHOP. D) determine whether CHOP plays a role in inducing aflatoxin and aldehyde reductase by testing the effect of CHOP overexpression and deficiency, and known CHOP-inducing agents on the of the reductases expression. e) clone and sequence aflatoxin reductase promoter and examine it for a CHOP-binding element and response elements described to direct antioxidant induction in other detoxification genes. Understanding the nature and mechanism of regulation of aldehyde and aflatoxin reductase expression will potentially assist in the prevention of harmful and carcinogenic effects of toxic aldehydes as well as provide a basis for identifying populations with increased susceptibility to certain environmental agents.