Immunocytochemical identification of DNA adducts, O6-methylguanine and 7-methylguanine, in respiratory and other tissues of rat, mouse and Syrian hamster exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
The present paper reports about an immunocytochemical inventory of the cell types involved in the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to a DNA methylating metabolite. The formation and distribution of the methylated DNA bases O6-methylguanine (O6-meGua) and 7-methylguanine (7-MeGua) were studied in respiratory tissues, oesophagus, liver, kidneys, pancreas, small intestine, colon and prostate of rat, mouse and hamster 6 h after treatment with a single dose of 30 mg NNK/kg. The tissue- and cell-specific distribution of O6-meGua- and 7-meGua-specific nuclear staining showed the same patterns and were remarkably similar in rat, mouse and hamster in spite of the diverging spectra of NNK-induced tumours in these species. In nasal tissue, a target for NNK-induced tumourigenesis in rat and hamster, but not in mouse, adduct-specific nuclear staining was observed in all three species in sustentacular cells, Bowman glands, respiratory epithelial cells and serous glands. Both methylated DNA bases were also observed in basal cells of the olfactory epithelium of rat and (occasionally) hamster, but not in those of the mouse. In the trachea, a target for NNK-induced tumourigenesis in hamster only, substantial adduct-specific nuclear staining was found in basal epithelial and glandular cells of the hamster; in the same cells of rat and mouse only a weak nuclear staining was found. In the lung, a common target for NNK-induced tumourigenesis, the formation of O6-meGua and 7-meGua was restricted predominantly to bronchial and proximal bronchiolar epithelium. Nuclear staining in the rat was occasionally found in alveolar cells and was also observed in hepatocytes. In the three species investigated, O6-meGua- and 7-MeGua-specific nuclear staining was found in target and non-target tissues. Apparently, and in analogy with results obtained in other studies, the species-specific organotropy for tumour formation of NNK is not exclusively determined by DNA methylation. Expanding methylation data with literature data on factors considered to be involved in tumour formation, namely proliferation, toxicity and DNA repair among others, still did not lead to a satisfactory explanation for the species-specific organotropy observed. Additional factors (yet to be identified), need to be taken into account in order to explain (and predict) tumourigenic effects induced by monofunctional methylating agents.
Van Benthem
J
J
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
Feron
V J
VJ
Leeman
W R
WR
Wilmer
J W
JW
Vermeulen
E
E
den Engelse
L
L
Scherer
E
E
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D002467:Cell Nucleus / Q000737:chemistry; D006224:Cricetinae; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D018736:DNA Adducts / Q000032:analysis* / Q000378:metabolism; D004249:DNA Damage; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008297:Male; D008647:Mesocricetus; D008745:Methylation; D051379:Mice; D009296:Nasal Cavity / Q000737:chemistry; D009602:Nitrosamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000737:chemistry*; D013194:Staining and Labeling / Q000379:methods; D014132:Trachea / Q000737:chemistry
D002273:Carcinogens; D018736:DNA Adducts; D009602:Nitrosamines; D006147:Guanine; C008450:7-methylguanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004247:DNA; C008449:O-(6)-methylguanine