Sex differences in the formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in CDF1 mice.
The potent food mutagen 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ) is carcinogenic in the CDF1 mouse, affecting the liver, lungs and forestomach. Females are approximately twice as sensitive as males to liver tumor induction. Using 32P-postlabeling assays, the dose-response of IQ-DNA adduct formation was determined in various organs of male and female CDF1 mice after single p.o. doses of IQ. To determine the possible correlation between IQ-DNA adduct formation, persistence and tumorigenicity in target organs, young adult male and female CDF1 mice were treated with a single p.o. dose (50 mg/kg) of IQ, and IQ-DNA adducts were isolated and quantitated in liver, lungs, forestomach, small intestine and large intestine over a 24 day period. In the range of 5-50 mg IQ/kg, IQ-DNA adduct formation was related to dose in all organs examined (liver, lungs, stomach, small intestine, large intestine). Total adduct formation (expressed as relative adduct labeling, RAL) 24 h after administration was highest in the liver (6.4-6.9 x 10(-7)) with lower levels, in decreasing order, in the large intestine, small intestine (non-target organs), forestomach and lungs (target organs). In all cases the major adduct, comprising 68-79% of the total, co-chromatographed with standard N-(deoxyguanosin-8-yl)-IQ. Up to three additional IQ-specific adducts could be detected. Except in the liver, adduct levels 24 h after administration of IQ were 2- to 3-fold higher in females than in males. There was no preferential retention of any one of the four adducts 1-24 days after administration of IQ. Beyond day 4 after administration, total adducts in the liver of females were approximately 2-fold higher than those in males, and the rate of removal from female lung was approximately 2-fold faster than that from male lung during the 1-24 day time period. Both these findings correspond to the known sex differences in IQ-induced tumor incidences in these organs. The higher adduct levels in non-target organs (intestines) as compared to target organs (lungs and stomach), combined with the absence of differential persistence of any individual adduct indicates that, in addition to adduct formation and persistence, other factors contribute to the target organ specificity of IQ in CDF1 mice.
Department of Pathology, Medical College of Ohio, Toledo 43699.
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D000818:Animals; D001345:Autoradiography; D002273:Carcinogens / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D007420:Intestine, Large / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011804:Quinolines / Q000494:pharmacology*; D012737:Sex Factors; D013997:Time Factors
D002273:Carcinogens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA