Preferential methylation of target organ DNA by the oesophageal carcinogen N-nitrosomethylbenzylamine.
Male Wistar rats received a single i.v. injection of the oesophageal carcinogen N-nitroso[methyl-14C]-methylbenzylnitrosamine (2.5 mg/kg body weight). Rapid distribution of the carcinogen occurred, with highest initial concentrations in liver and kidney. Within 10 min after the injection, 14C-labelled metabolites accounted for 50% of the total radioactivity present in the oesophagus, for approximately 25% in liver and forestomach, and for less than 20% in all other organs investigated. Decay of the carcinogen in rat serum followed first-order kinetics with a half-life of 35 min. Of the total radioactivity administered, 49% was exhaled as 14CO2 within 10 h and an additional 5-10% was excreted via urine and faeces. Four hours after a single i.v. injection of N-nitroso-[methyl-14C]benzylnitrosamine methylation of purine bases in DNA was most extensive in the oesophagus, followed by liver, lung and forestomach DNA. In the remaining tissues, DNA methylation was either considerably less (kidney, glandular stomach, spleen) or not at all detectable (ileum, colon, brain). At this time the concentration of the promutagenic base O6-methylguanine in oesophageal DNA was six times higher than in lung and nine times higher than in hepatic DNA. These data suggest that in the rat the selective induction of oesophageal tumours by N-nitrosomethylbenzylamine and related asymmetrical nitrosamines is mediated by a preferential bioactivation of the carcinogen in the target organ.
Hodgson
R M
RM
Abteilung Neuropathologie, Pathologisches Institut der Universität Freiburg, GFR.
Wiessler
M
M
Kleihues
P
P
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D019175:DNA Methylation; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D004938:Esophageal Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D002273:Carcinogens; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine