DNA adduct formation of the food-derived mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates undergoing carcinogen bioassay.
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 10(7) bases), followed by kidney (0.53-1.16 adducts per 10(7) bases), with comparable adduct levels detected in colon, heart, and pancreas (0.15-0.40 adducts per 10(7) 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.
Turesky
R J
RJ
Research Centre, Nestec Ltd., Lausanne, Switzerland.
Gremaud
E
E
Markovic
J
J
Snyderwine
E G
EG
D000818:Animals; D015197:Carcinogenicity Tests; D018736:DNA Adducts / Q000096:biosynthesis* / Q000378:metabolism*; D005260:Female; D006147:Guanine / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity*; D011804:Quinolines / Q000378:metabolism* / Q000633:toxicity*
D018736:DNA Adducts; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D006147:Guanine