Davis C D, Schut H A, Snyderwine E G
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892.
Carcinogenesis. 1994 Apr;15(4):641-5. doi: 10.1093/carcin/15.4.641.
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.
杂环胺2-氨基-3-甲基咪唑并[4,5-f]喹啉（IQ）和2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是可形成DNA加合物的致癌物。在本研究中，我们采用32P后标记法，测定单次给予（100 mg/kg，口服）或10次给予任一致癌物后，Fischer-344大鼠肝细胞核DNA和线粒体DNA中IQ和PhIP加合物的水平。单次给予IQ后，肝细胞核中加合物水平比线粒体DNA中的高2倍以上；然而，重复给予IQ后，核DNA和线粒体DNA中的加合物水平无显著差异。相比之下，单次给予PhIP后，核DNA和线粒体DNA中的加合物水平无显著差异；然而，多次给予PhIP后，线粒体DNA中的加合物水平显著高于核DNA中的。核DNA和线粒体DNA中单个IQ或PhIP加合物的百分比不同，尤其是在给予10次剂量后。对于IQ，C8-鸟嘌呤加合物在核DNA的总IQ加合物水平中占72%，但在线粒体DNA的总加合物水平中仅占40%。给予10次PhIP后，C8-鸟嘌呤加合物在核DNA和线粒体DNA的总加合物水平中分别占48%和15%。此外，一种未鉴定的PhIP加合物在核DNA中的百分比为14%，但在线粒体DNA中<1%。单次给予任一化合物后3、24、120和240小时，单个加合物的百分比大致相同，尽管两个细胞器中IQ和PhIP的总加合物水平似乎随时间下降。IQ和PhIP线粒体DNA加合的意义以及不同杂环胺加合物对致癌作用的影响值得进一步研究。
