Turesky R J, Gremaud E, Markovic J, Snyderwine E G
Research Centre, Nestec Ltd., Lausanne, Switzerland.
Chem Res Toxicol. 1996 Mar;9(2):403-8. doi: 10.1021/tx950132j.
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.
在食蟹猴中研究了2-氨基-3-甲基咪唑并[4,5-f]喹啉（IQ）的DNA加合物形成情况。单次口服剂量IQ（20mg/kg）24小时后，通过32P后标记法检测的DNA加合物的模式和分布在所有组织中相似。肝脏中发现的DNA加合物水平最高（每10^7个碱基有3.67 - 11.19个加合物），其次是肾脏（每10^7个碱基有0.53 - 1.16个加合物），结肠、心脏和胰腺中的加合物水平相当（每10^7个碱基有0.15 - 0.40个加合物）。两种2'-脱氧鸟苷（dG）加合物约占所有组织中观察到的损伤的90%。N-（脱氧鸟苷-8-基）-2-氨基-3-甲基咪唑并[4,5-f]喹啉（dG-C8-IQ）是主要加合物，约占加合物的50 - 80%，其次是5-（脱氧鸟苷-N2-基）-氨基-3-甲基咪唑并[4,5-f]喹啉（dG-N2-IQ），占加合物的20 - 40%。还在进行致癌生物测定的动物中研究了DNA加合物的形成，给予IQ的剂量为10或20mg/kg，每周5天，持续长达9.2年。在长期治疗的动物中，胰腺、肾脏和心脏中的DNA加合物水平平均比单次给药的动物中观察到的水平增加了40至90倍，而结肠和肝脏中的加合物仅增加了3至10倍。在长期治疗期间，所有缓慢分裂组织中dG-N2-IQ对总DNA加合物的贡献急剧增加，并且dG-N2-IQ成为主要损伤。在细胞分裂率高的结肠中没有dG-N2-IQ的优先积累，dG-C8-IQ仍然是主要损伤。这些发现表明在缓慢分裂组织中酶修复系统优先去除dG-C8-IQ加合物。dG-N2-IQ和dG-C8-IQ各自的作用以及加合物修复在IQ强大的肝癌致癌性中的参与，值得进一步研究。
