Dietary heterocyclic amines as potential human carcinogens: experimental data from nonhuman primates.
During the cooking of meats, several highly potent mutagenic heterocyclic amines (HCAs) are produced. To date, 10 HCAs have been shown to be carcinogenic in rodents, and one HCA, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), has been shown to be a potent hepatocarcinogen in nonhuman primates. In this report, we discuss the role of metabolic activation and DNA adduct formation in the carcinogenicity of HCAs, especially in nonhuman primates. The potent hepatocarcinogenicity of IQ in cynomolgus monkeys appears to be associated with the in vivo metabolic activation of IQ and the formation of hepatic DNA adducts. Notably, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx), is poorly metabolically activated in monkeys and lacks the potency of IQ to induce hepatocellular carcinoma. Ongoing studies with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), indicate that PhlP is metabolically activated in monkeys and is a likely carcinogen in this species. We further compared human, rat, and cynomolgus monkey hepatic microsomes for their abilities to metabolically activate various HCAs to mutagens. Our in vitro results show that humans, relative to rats or cynomolgus monkeys, have a good capacity to metabolically activate the HCAs. These findings support the concept that humans are likely to be susceptible to the carcinogenic effects of HCAs.
Thorgeirsson
U P
UP
Division of Basic Science, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Snyderwine
E G
EG
Gomez
D E
DE
Adamson
R H
RH
D000588:Amines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology; D006912:Hydroxyquinolines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D009153:Mutagens / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats
D000588:Amines; D002273:Carcinogens; D018736:DNA Adducts; D006571:Heterocyclic Compounds; D006898:Hydroxylamines; D006912:Hydroxyquinolines; D007093:Imidazoles; D009153:Mutagens; D011810:Quinoxalines; C060373:2-amino-3-methylimidazo(4,5-f)-quinoline 5-sulfate ester; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine