Accumulation of O6- and 7-methylguanine in DNA of N-nitroso-N-methylbenzylamine-treated rats is restricted to non-target organs for N-nitroso-N-methylbenzylamine-induced carcinogenesis.
The distribution and accumulation of O6-methylguanine (O6-meGua) and 7-methylguanine (7-meGua) was investigated immunocytochemically in target and non-target tissues of rats injected twice weekly with 0.5 mg N-nitroso-N-methylbenzylamine (NMBzA)/kg for 16.5 weeks. Seventy two hours after every two or three doses, two NMBzA-treated rats and one control rat were killed. Tissue-specific cell proliferation was investigated after two injections of bromodeoxyuridine (BrdU) to rats unexposed to NMBzA. Neither O6-meGua- nor 7-meGua-specific immunostaining could be observed in the target tissues for tumor induction, i.e. esophagus, tongue and forestomach. Accumulation of both O6-meGua and 7-meGua was found, however, in nasal, tracheal and bronchiolar epithelia and glands--tissues for which tumor induction by NMBzA has not been reported. An explanation for this phenomenon might be the relatively low levels of cellular proliferation we observed in the latter epithelia. The present results support the hypothesis that the tumorigenic organotropism of NMBzA is determined both by the level of DNA methylation and the proliferative capacity of the methylated cells.
Van Benthem
J
J
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), Amsterdam.
Vermeulen
E
E
Winterwerp
H H
HH
Wild
C P
CP
Scherer
E
E
Den Engelse
L
L
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000633:toxicity; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D002273:Carcinogens; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C014707:nitrosobenzylmethylamine; C008449:O-(6)-methylguanine; D004128:Dimethylnitrosamine