Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat and nonhuman primates.
The formation and persistence of the two principal DNA adducts of the food derived carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) have been investigated in rats and nonhuman primates. DNA adduct formation in the liver of male Fischer-344 rats occurred in a dose-dependent manner (0.01-20 mg/kg) where N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-C8-IQ) and 5-(deoxyguanosin-N2-yl)-2-amino-3-methylimidazo[4,5-f] quinoline (dG-N2-IQ) accounted for approximately 60-80% and 20-40%, respectively, of the total adducts observed by 32P postlabeling. Similar DNA adduct profiles were observed in kidney and colorectal tissue of rats given a single oral dose of IQ (20 mg/kg) which, when given chronically to this species, results in tumorigenesis in liver and colorectum, but not in kidney. dG-C8-IQ was removed more rapidly than dG-N2-IQ from liver and kidney, but removal of both adducts from the colorectum closely followed cell replication. Similar DNA adduct profiles were observed in liver and extrahepatic tissues of nonhuman primates following a single dose of IQ (20 mg/kg). In chronically treated monkeys undergoing carcinogen bioassay, there was a sharp increase in the contribution of dG-N2-IQ to total DNA adducts in all slowly dividing tissues. There was no preferential accumulation of dG-N2-IQ in the colon, a tissue with a high rate of cell division, and dG-C8-IQ remained the predominant lesion. These findings point to a preferential removal of the dG-C8-IQ adduct by enzyme repair system(s) in slowly dividing tissues in both rats and nonhuman primates.
Turesky
R J
RJ
Nestec Ltd., Lausanne, Switzerland. turesky@chlsnr.nestrd.ch
Box
R M
RM
Markovic
J
J
Gremaud
E
E
Snyderwine
E G
EG
D000818:Animals; D003106:Colon / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D018736:DNA Adducts; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline