SPECIES-DIFFERENCES IN METABOLISM OF HETEROCYCLIC AROMATIC-AMINES, HUMAN EXPOSURE, AND BIOMONITORING

Heterocyclic aromatic amines (HAAs) are animal carcinogens and suspect ed human carcinogens which are formed in cooked foods at the low parts per billion level. HAAs in cooked meats were purified by either immun oaffinity chromatography or solid phase tandem extraction, which allow ed for the simultaneous analysis of 11 HAAs by HPLC. The metabolism of two prominent HAAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxafine (Me lQx) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was investigate d in animal models and in vitro with human tissues to develop strategi es for human biomonitoring. MelQx and IQ are rapidly absorbed from the gastrointestinal tract of rodents and transformed into several detoxi fication products which are excreted in urine and feces. Metabolites r esult from cytochrome P450-mediated ring oxidation at the C-5 position followed by conjugation to sulfate or beta-glucuronic acid. Other maj or metabolites include the phase II conjugates, N-2-glucuronide and N- 2-sulfamate. A metastable N-2-glucuronide conjugate of the genotoxic m etabolite of N-hydroxy-MelQx was also detected in urine and bile. The binding of both carcinogens to blood proteins was low and suggests tha t human biomonitoring through protein adducts may be difficult. These metabolic pathways exist in nonhuman primates and several of these pat hways also occur in vitro with human liver. The urinary excretion of M elQx in seven human subjects following consumption of cooked beef or f ish ranged between 2 and 22 ng in 12 hr when determined by negative io n chemical ionization GC-MS. After acid hydrolysis of urine, the amoun t of MelQx increased 4- to 10-fold in 6 of the 7 subjects. These acid labile metabolites were identified as the N-2-sulfamate and N-2-glucur onide following column chromatography and HPLC purification. Thus, ami ne sulfamation and N-2-glucuronidation are important routes of detoxif ication of MelQx in rodents, nonhuman primates, and humans.