Kokkinakis D M
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611.
Carcinogenesis. 1992 May;13(5):759-65. doi: 10.1093/carcin/13.5.759.
Levels of methyl and hydroxypropyl adducts induced by single s.c. injections of various doses of tritium-labeled N-nitrosobis(2-hydroxypropyl)amine ([1-3H]BHP) were determined in the liver, pancreas, kidney and lung of hamsters and rats. At doses of BHP used in carcinogenesis studies (100-500 mg/kg), methylation of DNA was more extensive than its hydroxypropylation; however, it did not increase proportionally with the dose and gradually became secondary to hydroxypropylation at higher doses of the carcinogen. Ratios of hydroxypropyl versus methyl adducts also varied significantly depending on the tissue and species. In both species ratios of N7-hydroxypropylguanine (N7-HpG) versus N7-methylguanine (N7-MeG) were greater in kidney and pancreas than in liver or lung. Due to apparent differences in the repair of O6-methylguanine (O6-MeG) and O6-hydroxypropylguanine (O6-HpG), and the propensity of 2-hydroxypropylating as compared to methylating agents to yield a greater percentage of oxygen adducts, ratios of O6-HpG versus O6-MeG were markedly greater than those of N7-HpG versus N7-MeG. Levels of O6-HpG were greater than those of O6-MeG in rat liver, pancreas and kidney and also in hamster kidney, while such levels were similar in rat lung and also in hamster liver, pancreas and lung. Like N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), BHP was activated primarily in the liver and induced substantially greater DNA damage in this than in any other tissue examined. However, unlike BOP and HPOP, which induced similar levels of hepatic DNA damage in the above two species, BHP methylated and hydroxypropylated hamster liver DNA more extensively than that of the rat. Differences between BOP and BHP were also observed regarding levels and distribution of DNA adducts in extrahepatic tissues. In rats, BHP induced greater levels of methylation and hydroxypropylation in lung than in kidney, while the reverse was observed with BOP. Apparently reduction of the beta-carbon of pancreas-specific nitrosamine carcinogens results in a shift of alkylation from kidney to the lung. Excretion of HPOP in the urine of BHP-treated animals and the observed saturation of DNA methylation at high doses of BHP, supported the hypothesis that the BHP-induced methylation of DNA proceeded via the intermediate formation of HPOP. This was further supported by the observation that both excretion of HPOP and levels of methyl adducts were greater in hamsters than in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
通过皮下注射不同剂量的氚标记的N-亚硝基双（2-羟丙基）胺（[1-³H]BHP），测定了仓鼠和大鼠肝脏、胰腺、肾脏和肺中甲基和羟丙基加合物的水平。在致癌研究中使用的BHP剂量（100 - 500mg/kg）下，DNA的甲基化比羟丙基化更广泛；然而，它并不随剂量成比例增加，在较高剂量的致癌物作用下逐渐成为羟丙基化的次要反应。羟丙基与甲基加合物的比例也因组织和物种的不同而有显著差异。在这两个物种中，肾脏和胰腺中N7-羟丙基鸟嘌呤（N7-HpG）与N7-甲基鸟嘌呤（N7-MeG）的比例均高于肝脏或肺。由于O6-甲基鸟嘌呤（O6-MeG）和O6-羟丙基鸟嘌呤（O6-HpG）修复的明显差异，以及与甲基化剂相比，2-羟丙基化剂产生更高比例氧加合物的倾向，O6-HpG与O6-MeG的比例明显大于N7-HpG与N7-MeG的比例。大鼠肝脏、胰腺和肾脏以及仓鼠肾脏中O6-HpG的水平高于O6-MeG，而在大鼠肺以及仓鼠肝脏、胰腺和肺中，这些水平相似。与N-亚硝基双（2-氧代丙基）胺（BOP）和N-亚硝基（2-羟丙基）（2-氧代丙基）胺（HPOP）一样，BHP主要在肝脏中被激活，并且在肝脏中诱导的DNA损伤比在任何其他检测的组织中都要大得多。然而，与在上述两个物种中诱导相似水平肝脏DNA损伤的BOP和HPOP不同，BHP对仓鼠肝脏DNA的甲基化和羟丙基化作用比大鼠更广泛。在肝外组织中DNA加合物的水平和分布方面也观察到了BOP和BHP之间的差异。在大鼠中，BHP在肺中诱导的甲基化和羟丙基化水平高于肾脏，而BOP则相反。显然，胰腺特异性亚硝胺致癌物β-碳的减少导致烷基化从肾脏转移到肺。BHP处理动物尿液中HPOP的排泄以及在高剂量BHP下观察到的DNA甲基化饱和，支持了BHP诱导的DNA甲基化通过HPOP的中间形成进行的假设。仓鼠中HPOP的排泄和甲基加合物的水平均高于大鼠，这一观察结果进一步支持了这一假设。（摘要截断于400字）
