DNA damage produced by N-nitrosomethyl(2-oxopropyl)amine (MOP) in hamster and rat pancreas: a role for the liver.
DNA damage produced by N-nitrosomethyl(2-oxopropyl)amine (MOP) in hamster and rat pancreas: a role for the liver.
复制标题
N-亚硝基甲基（2-氧代丙基）胺 (MOP) 在仓鼠和大鼠胰腺中产生的 DNA 损伤：对肝脏的作用。
DOI：
10.1093/carcin/5.5.565
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发表时间：
1984
期刊：
影响因子：
4.7
通讯作者：
Curphey,TJ
中科院分区：
文献类型：
--
作者：
Schaeffer,BK;Wiebkin,P;Longnecker,DS;Coon,CI;Curphey,TJ
应用碱性洗脱分析技术，研究了胰腺癌强致癌物N-亚硝基甲基（2-氧代丙基）胺（MOP）对大鼠和仓鼠胰腺DNA的损伤作用。从暴露于以7-60 mg/kg的剂量腹膜内给予MOP 1小时的仓鼠中分离的胰腺DNA显示出剂量相关的DNA损伤。在接受20 - 180 mg MOP/kg的大鼠胰腺中观察到类似的剂量反应，表明仓鼠的敏感性是大鼠的2-3倍。与体内实验结果相反，大鼠和仓鼠胰腺腺泡细胞在体外暴露于与体内浓度相当的MOP（20-180 μ/ml）时，均未出现剂量相关的DNA损伤。用细胞色素P-450活性的诱导剂5，6-苯并异丁酮预处理的仓鼠腺泡细胞显示出大大增强的药物代谢能力，但在暴露于MOP后再次没有观察到DNA损伤。切碎的仓鼠或大鼠胰腺也未显示响应于MOP处理的DNA损伤。当仓鼠肝血供中断结扎给予60毫克/公斤的MOP静脉注射，并在15分钟后处死，胰腺和肝脏DNA的损害是可比的，在结扎对照组只收到生理盐水。给假手术动物施用MOP在15分钟时导致胰腺和肝脏的广泛DNA损伤。显示与假手术未结扎动物相比，肝脏结扎动物胰腺中MOP的量几乎增加。结扎动物的肝脏中不存在MOP。这些实验强烈表明，MOP对胰腺腺泡细胞以及可能对其他胰腺细胞类型的DNA损伤需要肝脏的代谢活化。
Utilizing the technique of alkaline elution analysis, the ability of N-nitrosomethyl(2-oxopropyl)amine (MOP), a potent pancreatic carcinogen, to damage pancreatic DNA in rats and hamsters was examined. Pancreatic DNA isolated from hamsters exposed for 1 h to MOP given i.p. at doses of 7–60 mg/kg showed dose-related DNA damage. A similar dose-response was observed in the pancreas of rats receiving 20 — 180 mg MOP/kg, suggesting that hamsters were 2–3 times more sensitive than rats. In contrast to the results obtainedin vivo, functionally viable acinar cells from both rat and hamster pancreas, when exposedin vitroto levels of MOP comparable to thosein vivo(20–180 μ/ml), failed to show dose-related DNA damage. Acinar cells from hamsters pretreated with 5, 6-benzoflavone, an inducer of cytochrome P-450 activity, showed greatly enhanced drug-metabolizing capability, but again no DNA damage was observed upon exposure to MOP. Minced hamster or rat pancreas also failed to show DNA damage in response to MOP treatment. When hamsters in which hepatic blood supply was interrupted by ligation were given 60 mg/kg MOP i.v. and sacrificed 15 min later, damage to pancreatic and liver DNA was comparable to that observed in ligated controls which had received saline only. Administration of MOP to sham-operated animals led to extensive DNA damage in both pancreas and liver at 15 min. Analysis by h.p.l.c. showed an almost Mold increase in the amount of MOP present in the pancreases of the liver-ligated animals as compared to the sham-operated unligated animals. MOP was absent from the liver of the ligated animals. These experiments strongly suggest that DNA damage by MOP to the pancreatic acinar cells and probably to other pancreatic cell types, as well, requires metabolic activation by the liver.