Heterocyclic arylamine food mutagen-carcinogens comprise a group of compounds isolated from cooked proteinaceous foods and as pyrolysis products of amino acids and proteins. These compounds are among the most mutagenic compounds yet tested in the Ames Salmonella mutagenicity assay. Studies in our laboratory with recombinant cytochrome P-450 have shown that HAAs undergo metabolic activation by a specific cytochrome P-450. The mutagenic metabolites generated upon cytochrome P-450 metabolism of these compounds are N-hydroxylamines which covalently bind to DNA directly and following further activation by transferases. Adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) have been examined in rodents and monkeys and found to be identical to those formed in vitro upon reaction of N-hydroxy-IQ with DNA, and those found in Salmonella. In addition to in vitro studies of HAA metabolism were are studying the in vivo metabolism and distribution of HAAs in monkeys. IQ is extensively metabolized in monkeys and excreted into urine and feces as metabolites. N-Sulfation, glucuronidation and N-demethylation play important roles in the detoxification and excretion of this compound. We have recently developed techniques for examining DNA adducts of HAA and their repair in specific genes using the UvrABC excinuclease. Initial studies are being conducted with cell cultures and purified DNA reacted in vitro with N-hydroxy-IQ. With this methodology we are seeing heterogeneity in initial adduct formation in different gene regions.
