Ruchirawat M, Mostafa M H, Shank R C, Weisburger E K
Carcinogenesis. 1983;4(5):537-9. doi: 10.1093/carcin/4.5.537.
The effect of CCl4 pretreatment (dose range from 0.5 to 2.0 ml/kg body weight) on the pathways of dimethylnitrosamine (DMN) metabolism was investigated. The oxidative-N-demethylation by the enzymes, DMN-demethylase I and II operating at low (4 mM) and high (200 mM) substrate concentration, respectively, was greatly reduced in a dose-dependent manner. In addition, the generation of an electrophilic intermediate capable of methylating DNA, specifically at the N-7 and O-6 positions of guanine, was completely inhibited by CCl4 (0.5 ml/kg body weight) pretreatment. When indole feeding (1% in the diet for 8 days prior to CCl4 administration) was employed as a means to enhance DMN-demethylase activities, it was found that the reduction of DMN-demethylase activities was more pronounced in these rats than in the controls. In agreement with earlier findings, 7-methylguanine and O6-methylguanine were not detectable in the CCl4 pretreated group. These results suggest that CCl4 exerts a strong inhibitory action on hepatic DMN metabolism, in particular on the pathway leading to alkylation of DNA guanine. This phenomenon may explain the protective role of CCl4 against DMN-induced hepatotoxicity and perhaps, carcinogenicity, believed to be closely associated with the abnormal modifications of DNA.
研究了四氯化碳预处理（剂量范围为0.5至2.0毫升/千克体重）对二甲基亚硝胺（DMN）代谢途径的影响。分别在低底物浓度（4毫摩尔）和高底物浓度（200毫摩尔）下起作用的DMN - 脱甲基酶I和II所介导的氧化N - 脱甲基作用，以剂量依赖的方式大幅降低。此外，四氯化碳（0.5毫升/千克体重）预处理完全抑制了能够使DNA甲基化的亲电中间体的生成，特别是在鸟嘌呤的N - 7和O - 6位置。当采用吲哚喂养（在给予四氯化碳前8天，饮食中含1%）作为增强DMN - 脱甲基酶活性的手段时，发现这些大鼠中DMN - 脱甲基酶活性的降低比对照组更明显。与早期研究结果一致，在四氯化碳预处理组中未检测到7 - 甲基鸟嘌呤和O6 - 甲基鸟嘌呤。这些结果表明，四氯化碳对肝脏DMN代谢具有强烈的抑制作用，特别是对导致DNA鸟嘌呤烷基化的途径。这种现象可能解释了四氯化碳对DMN诱导的肝毒性以及可能的致癌性的保护作用，据信这与DNA的异常修饰密切相关。
