Adduction of the heterocyclic amine food mutagens IQ and PhIP to mitochondrial and nuclear DNA in the liver of Fischer-344 rats.

Abstract

The heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogens that form DNA adducts. In the present study, we used the 32P-postlabeling method to measure the levels of IQ and PhIP adducts in hepatic nuclear and mitochondrial DNA of Fischer-344 rats given a single dose (100 mg/kg, p.o.) or 10 doses of either carcinogen. After a single dose of IQ, adduct levels were > 2-fold higher in hepatic nuclear than in mitochondrial DNA; however, after repeated IQ exposure, the levels of adducts in nuclear and mitochondrial DNA were not significantly different. In contrast, after a single dose of PhIP, there were no significant differences in adduct levels in nuclear and mitochondrial DNA; however, after multiple doses of PhIP, adduct levels were significantly higher in mitochondrial DNA than in nuclear DNA. The percentages of individual IQ or PhIP adducts were different between nuclear DNA and mitochondrial DNA, particularly after 10 doses. With IQ, the C8-guanine adduct accounted for 72% of the total IQ adduct levels in nuclear DNA but only 40% of total adduct levels in mitochondrial DNA. After 10 doses of PhIP, the C8-guanine adduct accounted for 48% and 15% of total adduct levels in nuclear DNA and mitochondrial DNA respectively. In addition, the percentage of an uncharacterized PhIP adduct was 14% in nuclear DNA but < 1% in mitochondrial DNA. The percentages of individual adducts were approximately the same 3, 24, 120 and 240 h after a single dose of either compound, though total IQ and PhIP adduct levels appeared to decline over time in both organelles. The significance of IQ and PhIP mitochondrial DNA adduction and the influence of distinct heterocyclic amine adducts on carcinogenesis merit further investigation.