Alkylation of rodent tissue DNA induced by N-nitrosobis(2-hydroxypropyl)amine.
Alkylation of rodent tissue DNA induced by N-nitrosobis(2-hydroxypropyl)amine.
复制标题
N-亚硝基双（2-羟丙基）胺诱导啮齿动物组织 DNA 的烷基化。
DOI：
10.1093/carcin/13.5.759
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发表时间：
1992
期刊：
影响因子：
4.7
通讯作者：
Kokkinakis,DM
中科院分区：
文献类型：
--
作者：
Kokkinakis,DM
单次皮下注射诱导的甲基和羟丙基加合物水平。用氚标记的N-亚硝基双（2-羟丙基）胺（[1- 3 H]BHP）对仓鼠和大鼠的肝、胰、肾和肺进行了不同剂量的注射。在致癌性研究中使用的BHP剂量（100-500 mg/kg）下，DNA甲基化比羟丙基化更广泛;然而，它没有随剂量成比例增加，并且在较高剂量的致癌物下逐渐继发于羟丙基化。羟丙基与甲基加合物的比例也因组织和物种而异。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）的比值大于肝脏或肺。由于O 6-甲基鸟嘌呤（N7-MeG）和O 6-羟丙基鸟嘌呤（O 6-HpG）的修复作用存在明显差异，且与甲基化试剂相比，2-羟丙基化倾向于产生更大百分比的氧加合物，因此O 6-HpG与O 6-MeG的比率明显大于N7-HpG与N7-MeG的比率。在大鼠肝脏、胰腺和肾脏以及仓鼠肾脏中，O 6-HpG的水平高于O 6-MeG的水平，而在大鼠肺中以及仓鼠肝脏、胰腺和肺中，O 6-HpG的水平相似。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，并在肝脏中诱导比任何其他组织更大的DNA损伤。然而，与BOP和HPOP不同，BHP在上述两个物种中诱导相似水平的肝DNA损伤，BHP甲基化和羟丙基化仓鼠肝DNA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的β-碳的减少导致烷基化从肾转移到肺。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中间形成进行的假设。这一点得到了以下观察结果的进一步支持：仓鼠的HPOP排泄量和甲基加合物水平均高于大鼠。根据肝组织中的加合物水平，估计在100 mg/kg剂量下，仓鼠和大鼠肝脏中分别有39%和24%的BHP被首先氧化生成HPOP。
Levels of methyl and hydroxypropyl adducts induced by single s.c. injections of various doses of tritium-labeledN-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 ofN7-hydroxypropylguanine (N7-HpG) versusN7-methylguanine (N7-MeG) were greater in kidney and pancreas than in liver or lung. Due to apparent differences in the repair ofO6-methylguanine (N7-MeG) andO6-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. LikeN-nitrosobis(2-oxopropyl)amine (BOP) andN-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 BOPand 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 theβ-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 ofDNA 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. Based on levels of adducts in hepatic tissue, it was estimated that at a dose of 100 mg/kg 39 and 24% of the BHP activated in the liver of hamsters and rats respectively was firstoxidized to yield HPOP.