DNA adduct formation of heterocyclic amine isomers in rats

DESCRIPTION (provided by applicant): The frequent consumption of meats cooked well-done leads to an increased risk for colon and breast cancer;however, the etiological agents responsible for this risk remain to be elucidated. The Report on Carcinogens, Eleventh Edition, National Toxicology Program, concluded that heterocyclic aromatic amines (HAAs), which arise in grilled meats, are reasonably anticipated to be human carcinogens. Many epidemiological studies have implicated HAAs as specific etiological agents in these cancers. However, the reported associations of dietary factors and genetic polymorphism data can not confirm the relationships between specific chemical exposures and carcinogenesis. Moreover, the characterized HAAs account for less than 30% of the mutagenicity attributed to this class of chemicals in well-done grilled meats and other uncharacterized HAAs are present. Recently, we discovered 2-amino-1-7-dimethylimidazo[4,5-g]quinoxaline (7-MeIgQx), an isomer of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), a potent animal carcinogen. 7-MeIgQx, is the most mass-abundant, genotoxic HAA formed in grilled beef;however, its carcinogenic potential is unknown. Our long-term goal is to assess the cancer risk posed by HAAs, by establishing chemical markers that may distinguish individuals at different levels of risk. Given the high concentrations of 7-MeIgQx formed in cooked beef in relationship to 8-MeIQx or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), two HAAs that are believed to contribute to dietary-related cancers, we hypothesize that 7-MeIgQx is a significant contributor to the overall genotoxic burden and cancer risk posed by HAAs. The objective of this application is to provide preliminary toxicological data on the capacity of 7-MeIgQx to undergo bioactivation in vitro and bind to DNA in vivo in the rat. We will use highly sensitive accelerator mass spectrometry methods to measure DNA adduct yields of 7-MeIgQx in vivo and compare the yields to those of 8-MeIQx. The rationale is that data generated from these pilot studies will provide a preliminary assessment of the carcinogenic potential of 7-MeIgQx in comparison to 8-MeIQx, based on the carcinogen binding index. This proposed research is relevant to NIH's mission on public health: specific aims 1 and 2 will establish toxicological data on the genotoxic potential of 7-MeIgQx in relationship to its carcinogenic isomer, 8-MeIQx. The proposed DNA binding study in vivo of a newly discovered HAA is an innovative approach to provide a rapid, provisional assessment of the carcinogenic potential of 7-MeIgQx, which arises cooked beef in greater quantities than 8-MeIQx and PhIP. This discovery is highly significant since metabolites and DNA adducts of 7- MeIgQx could serve as biomarkers of exposure and risk assessment to this class of dietary carcinogens. PUBLIC HEALTH RELEVANCE: The proposed study will provide a provisional estimate of the carcinogenic potential of a newly discovered heterocyclic aromatic amine (HAA), 2-amino-1,7-dimethylimidazo[4,5-g]quinoxaline (7-MeIgQx). HAAs are believed to be human carcinogens and 7-MeIgQx is the most mass-abundant HAA formed in cooked meat. The research will allow us to determine the health risk of 7-MeIgQx in relationship to other HAAs present in the diet.