ACETYLATION PHARMACOGENETICS--ARYLAMINES AND DNA DAMAGE

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The major objective of this proposal is to test the hypotheses that genetic differences in the activation of arylamine carcinogens are important determinants of DNA damage and the formation of DNA-carcinogen adducts, and that DNA-adduct formation seen after short-term exposures to arylamine carcinogens is a valid indicator of susceptibility to carcinogenesis in a genetically defined animal model. To test the first hypothesis intact inbred and congenic mice of defined metabolic genotype will be exposed to 2-aminofluorene under a number of exposure conditions and the formation of 2-AF-DNA adducts in the target tissues (liver and bladder) will be measured. The second hypothesis will be tested by a separate in vivo study of the development of tumors in target tissues in acetylator congenic mice exposed to 2-AF. Additional objectives include determining if a polymorphism in N-oxidation of arylamines exists in mice and it is an important determinant of tissue and DNA damage from these compounds. The role of other enzymes of arylamine metabolism in modulating the risk of damage by this ubiquitous class of chemicals will also be examined. An important goal of this proposal is to establish inbred acetylator congenic mice as models for human colo-rectal cancer related to heterocyclic arylamine food mutagens. The inbred acetylator congenic mouse strains provide a unique resource for the investigations proposed because they enable a study of this hereditary trait isolated from other polymorphic traits affecting the disposition of and response to arylamines. The analysis of the consequences of arylamine exposure using this animal model should enable a more accurate assessment of the effects attributable to acetylator genes in relation to other genes than heretofore possible, and may also facilitate the acquisition of information about differences in susceptibility to human cancers of environmental origin that is stymied because of the ethical constraints and methodological difficulties that prevail.