Organ specificity in the microsomal activation and toxicity of N-nitrosomethylbenzylamine in various species.
The microsomal metabolism of the rat esophageal carcinogen N-nitrosomethylbenzylamine (NMBZA) at the methylene carbon atom to yield benzaldehyde was studied in various organs of a number of species to determine the role of metabolic activation in the carcinogenicity or toxicity of the nitrosamine. In the Sprague-Dawley rat, NMBZA was metabolized by microsomes from liver, lung, and esophageal mucosa. In the F344 rat and rabbit, metabolic activity was present in both liver and esophageal mucosa, the only tissues studied in these species. In contrast, in the Syrian hamster and BALB/cByJ mouse, NMBZA debenzylation was undetectable in the esophagus but occurred at relatively high rates in liver, lung, and kidney. The forestomach mucosa exhibited undetectable levels of activity in the Sprague-Dawley rat and BALB/cByJ mouse, although in the hamster, it was present at a very low level. Administration of a dose of NMBZA acutely toxic to the rat (18 mg/kg i.p.) resulted in significant cellular damage only to the rat esophageal mucosa, no other tissues examined in the rat, hamster, or mouse being affected. These observations, together with the available data on carcinogenicity of the nitrosamine in the rat and rabbit, suggest that in the esophagus, at least, metabolic activation of NMBZA is necessary to elicit its toxic and/or carcinogenic effect. However, NMBZA is also metabolized at a high rate in the liver of all species but is not toxic or carcinogenic in this tissue, suggesting that other factors besides metabolic activation must be involved in the resistance of hepatocytes to the effects of the nitrosamine. Microsomes prepared from human esophageal mucosa from six patients metabolized NMBZA at rates that were either undetectable or approximately 70 times lower than in the Sprague-Dawley rat.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D006224:Cricetinae; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004947:Esophagus / Q000378:metabolism; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009928:Organ Specificity; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity
D002273:Carcinogens; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine