MECHANISM OF ESOPHAGEAL TUMOR-INDUCTION IN RATS BY N-NITROSOMETHYLBENZYLAMINE AND ITS RING-METHYLATED ANALOG N-NITROSOMETHYL(4-METHYLBENZYL)AMINE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (7) , 2836-2840
Abstract
The metabolism of the esophageal carcinogen N-nitroso-methylbenzylamine (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 were 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 h, neither compound was detectable in serum. Within 12 h 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 h after a single i.v. injection (0.017 mmol/kg) of [methyl-14C]MBN was highest in the esophagus (344 .mu.mol 7-methylguanine/mol guanine), followed by liver, lung and forestomach. Considerbly less DNA methylation was produced by an equimolar dose of 4-MeMBN, with highest values in liver, followed by esophagus (22 .mu.mol 7-methylguanine/mol guanine) and lung. 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. The lower toxicity and carcinogenicity of 4-MeMBN after systemic administration may be 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. The bioactivation of these compounds may be initiated predominantly by hydroxylation at the methylene bridge leading to a methylating rather than a benzylating intermediate as the ultimate carcinogen.

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