Possible relationship between tissue distribution of DNA adducts and genotoxicity of food-derived heterocyclic amines.
During the past decade and a half, a number of potent mutagens belonging to the class of heterocyclic aromatic amines (HCA) have been isolated and identified from cooked fish, beef, fowl and other meat, and from beef extracts. Several of these HCA mutagens have also been found to be carcinogenic in rodent bioassays, and one of these compounds, 2-amino-3-methylimidazo-[4,5-f]-quinoline (IQ), has recently been found to cause hepatocellular carcinoma in cynomolgus monkeys. The potential etiological role of these mutagens and carcinogens in human cancer prompted us to evaluate the genotoxicity of these compounds in both nonhuman primates and rodents, with particular emphasis on the formation and tissue distribution of DNA adducts. We selected three compounds for this study based on several factors including chemical structure, mutagenic activity in vitro, concentration in cooked food, and carcinogenic activity in the rodent test system. These were IQ, 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (8-MeIQx), and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine (PhIP). To maximize the sensitivity of the DNA adduct measurements, we have employed the 32P-postlabeling method to analyze levels and tissue distribution of DNA adducts derived from IQ 8-MeIQx, and PhIP. We have measured DNA adduct formation for all three compounds in various tissues and white blood cells of monkeys following both acute and chronic administration. Both IQ and PhIP form high levels of adducts in a number of organs, particularly liver, kidney, and heart. In contrast, administration of 8-MeIQx to the cynomolgus monkeys results in the formation of only low adduct levels with many tissues showing no detectable levels of adducts. Studies in rodents have also shown that IQ and PhIP from DNA adducts in a number of organs in addition to those that are targets for carcinogenic effects of these agents. Although high DNA adduct levels of HCA are generally found in target organs for HCA induced carcinogenesis the widespread distribution of the adducts in organs not associated with the carcinogenic effects suggest that HCA exposure may be a possible etiological factor in cardiovascular diseases and other degenerative ailments.
Thorgeirsson
S S
SS
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Davis
C D
CD
Schut
H A
HA
Adamson
R H
RH
Snyderwine
E G
EG
D000588:Amines / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced; D002417:Cattle; D003296:Cooking; D018736:DNA Adducts / Q000378:metabolism*; D005399:Fishes; D006571:Heterocyclic Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D006358:Hot Temperature; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced; D008252:Macaca fascicularis; D008460:Meat; D009153:Mutagens / Q000378:metabolism* / Q000493:pharmacokinetics; D011200:Poultry; D011323:Primates; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution
D000588:Amines; D018736:DNA Adducts; D006571:Heterocyclic Compounds; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline