Hodgson R M, Schweinsberg F, Wiessler M, Kleihues P
Cancer Res. 1982 Jul;42(7):2836-40.
The metabolism of the esophageal carcinogen N-nitrosomethylbenzylamine (MBN) and its ring-methylated analog N-nitrosomethyl(4-methylbenzyl)amine (4-MeMBN) was investigated in male Wistar rats. When given in the drinking water, both compounds have been shown to induce a high incidence of esophageal carcinomas but, after systemic administration of equimolar doses, 4-MeMBN is considerably less toxic and carcinogenic than is MBN. Following a single i.v. injection, 4-MeMBN disappeared from serum faster than did MBN. After 5 hr, neither compound was detectable in serum. Within 12 hr after a single i.v. injection (0.017 mmol/kg) of [methyl-14C]-MBN, 49% of the radioactivity was exhaled as 14CO2, and less than 5% was in the urine, compared with only 13% as 14CO2 and 65% in the urine after an equimolar dose of 4-Me[methyl-14C]MBN. The urinary metabolite of 4-MeMBN was identified as its benzoic acid derivative. Methylation of DNA purines 4 hr after a single i.v. injection (0.017 mmol/kg) of [methyl-14C]MBN was highest in the esophagus (344 mumol 7-methylguanine per mol guanine), followed by liver, lung, and forestomach. Considerably less DNA methylation was produced by an equimolar dose of 4-MeMBN, with highest values in liver, followed by esophagus (22 mumol 7-methylguanine per mol guanine) and lung. However, s.c. injections of equitoxic doses of MBN (18 mg/kg) and 4-MeMBN (394 mg/kg) produced similar amounts of 7-methylguanine in esophageal nucleic acids. These data indicate that the lower toxicity and carcinogenicity of 4-MeMBN after systemic administration are due to the rapid formation (mainly in the liver) and excretion via the urine of its benzoic acid derivative. The strong carcinogenic effect of orally administered 4-MeMBN can be explained by direct uptake from the drinking water into the esophageal mucosa. Following a single i.v. injection (0.017 mmol/kg) of [methylene-14C]MBN and 4-Me[methylene-14C]MBN, no benzylated bases were detectable in rat tissues. This indicates that the bioactivation of these compounds is initiated predominantly by hydroxylation at the methylene bridge leading to a methylating rather than a benzylating intermediate as the ultimate carcinogen.
在雄性Wistar大鼠中研究了食管致癌物N-亚硝基甲基苄胺（MBN）及其环甲基化类似物N-亚硝基甲基（4-甲基苄基）胺（4-MeMBN）的代谢情况。当通过饮用水给予时，这两种化合物均已显示可诱发高发病率的食管癌，但是，在全身给予等摩尔剂量后，4-MeMBN的毒性和致癌性比MBN小得多。单次静脉注射后，4-MeMBN从血清中消失的速度比MBN快。5小时后，血清中均未检测到这两种化合物。单次静脉注射[甲基-14C]-MBN（0.017 mmol/kg）后12小时内，49%的放射性以14CO2形式呼出，尿液中不到5%，而等摩尔剂量的4-Me[甲基-14C]MBN注射后，只有13%以14CO2形式呼出，65%在尿液中。4-MeMBN的尿代谢产物被鉴定为其苯甲酸衍生物。单次静脉注射[甲基-14C]MBN（0.017 mmol/kg）4小时后，食管中DNA嘌呤的甲基化程度最高（每摩尔鸟嘌呤含344 μmol 7-甲基鸟嘌呤），其次是肝脏、肺和前胃。等摩尔剂量的4-MeMBN产生的DNA甲基化程度要低得多，肝脏中最高，其次是食管（每摩尔鸟嘌呤含22 μmol 7-甲基鸟嘌呤）和肺。然而，皮下注射等毒性剂量的MBN（18 mg/kg）和4-MeMBN（394 mg/kg）在食管核酸中产生的7-甲基鸟嘌呤量相似。这些数据表明，全身给药后4-MeMBN较低的毒性和致癌性是由于其苯甲酸衍生物在肝脏中快速形成并经尿液排泄。口服4-MeMBN的强致癌作用可以通过其从饮用水直接吸收进入食管黏膜来解释。单次静脉注射[亚甲基-14C]MBN和4-Me[亚甲基-14C]MBN（0.017 mmol/kg）后，在大鼠组织中未检测到苄基化碱基。这表明这些化合物的生物活化主要是通过亚甲基桥上的羟基化引发的，导致形成甲基化而非苄基化中间体作为最终致癌物。
