CARCINOGENESIS: HIGHLY REACTIVE NITROSAMINES

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The principal hypothesis of the proposed research is that environmentally prevalent B-nitrosaminos-ethanols are activated to carcinogens through their alcohol dehydrogenase mediated oxidation to reactive a-nitrosamino-aldehydes. These compounds readily transnitrosate primary and secondary amines and deaminate guanosine. Diazonium ions and glyoxal, both mutagenic components, are also produced from them, but their reaction with guanosine generates many products which remain to be determined. A second hypothesis is that hydrates of the alpha-nitrosamino-aldehydes may be substrates for sulfotransferase enzymes. The resulting sulfates are expected to rapidly produce reactive 3-alkyl-5-hydroxy-1,2,3,- oxadiazolinium ions, which upon proton loss could generate reactive oxadiaoline ylides which could also be produced from the ring-chain tautomerism of the parent aldehydes. These hypotheses and others for the carcinogenic activation of beta-hydroxynitrosamines will be tested by: 1. Determining the mechanism of the transnitrosation reaction. 2. Examining the reactions of nucleophiles, mild bases, and nucleosides with 3- alkyl-1, 2, 3-oxadiazolinium ions. 3. Determining how alpha- nitrosamino-aldehydes and compounds produced from them modify deoxy-oligonucleotides. 4. Determining through model chemical and biochemical studies whether B-hydroxynitrosamines are activated through the generation of alkoxy radicals, and 5. Determining the effects of specific enzyme inhibitors on the transformations of beta-hydroxynitrosamines and alpha-nitrosamino-aldehydes. This research is expect to go far toward establishing the mechanism by which B-nitrosamino-ethanols undergo carcinogenic activation and how direct action a-nitrosamino -aldehyde mutagens modify DNA.