Amongst the mutagens found in fried meat, 2-amino-3-methylimidazo [4,5-f] quinaline (IQ) is a representative compound. IQ has recently been shoun to be a powerful carcinogen in mice and in rats. A number of important target organs were affected in rats, including the intestinal tract, mammary gland, ear duct, and pancreas, as well as other organs to a lesser degree. Of relevance, is the specificity for intestinal tract and mammary gland since these findings underwrite the working hypothesis that IQ and related compounds may be the genotoxic, DNA-reactive carcinogens involved in human nutritional carcinogenesis. Based on current knowledge of the metabolism of related carcinogenic arylamines, the hypothesis can be formulated that IQ undergoes metabolism to a N-hydroxy derivative, or a N-acety 1-N-hydroxy derivative, further converted to a transport form such as a glucuronide. This complex may be hydrolyzed, and the released aglycone further metabolized to DNA-reactive forms in target tissues. Thus, research on the mode of action of IQ through detailed studies of its metabolism is of great contemporary importance. The overall fate of IQ will be studied using the isotopically labeled chemical in animals as a function of age, sex, and dosage of IQ. Furthermore, possible modification of metobolism by chronic exposure to IQ, fed for ten weeks and for six months, will be examined. Interaction with cellular macromolecules, including DNA will be determined, including binding as a function of dosage and time. Parallel studies will be conducted on cells and cell fractions, with initial emphasis on liver and intestinal tract, again in animals pretreated with unlabeled IQ and naive animals of the same age. The dosages used will include the level that induces cancer in animals and lower level. This approach is designed to provide key background information on the mode of action of a newly discovered class of carcinogens with extensive human intake.
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