DNA adduct formation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was investigated in cynomolgus monkeys. The pattern and distribution of DNA adducts examined by 32P-postlabeling were similar in all tissues 24 h after a single oral dose of IQ (20 mg/kg). The highest DNA adduct levels were found in the liver (3.67-11.19 adducts per 107 bases), followed by kidney (0.53-1.16 adducts per 107 bases), with comparable adduct levels detected in colon, heart, and pancreas (0.15-0.40 adducts per 107 bases). Two 2′-deoxyguanosine (dG) adducts accounted for approximately 90% of the observed lesions in all tissues. N-(Deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-C8-IQ) was the major adduct and accounted for approximately 50-80% of the adducts, followed by 5-(deoxyguanosin-N2-yl)-amino-3-methylimidazo[4,5-f]quinoline (dG-N2-IQ) which accounted for 20-40% of the adducts. DNA adduct formation was also investigated in animals undergoing carcinogen bioassay with IQ administered at 10 or 20 mg/kg, 5 days per week for up to 9.2 years. In chronically treated animals, the DNA adduct levels in pancreas, kidney, and heart increased on average by 40- to 90-fold over those observed in animals given a single dose, while only 3- to 10-fold increases in adducts were observed in colon and liver. A sharp increase in the contribution of dG-N2-IQ to total DNA adducts occurred in all slowly dividing tissues during chronic treatment, and dG-N2-IQ became the predominant lesion. 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. The respective roles of dG-N2-IQ and dG-C8-IQ, and the involvement of adduct repair in the potent hepatocarcinogenicity of IQ, merit further investigation.
|Original language||English (US)|
|Number of pages||6|
|Journal||Chemical Research in Toxicology|
|State||Published - Mar 1 1996|