In vivo treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces organ-specific alterations in in vitro repair of DNA pyridyloxobutylation.
To investigate the mechanisms responsible for inter-organ differences in susceptibility to 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK)-induced carcinogenesis, the objectives were to compare DNA repair activities of extracts from mouse lung and liver towards NNK-induced pyridyloxobutyl (POB) damage to plasmid DNA, and to determine if and the mechanism by which in vivo NNK treatment of mice alters DNA repair. Repair activity of POB adducts was three times greater in mouse liver than in mouse lung (P<0.05). Repair activities of lung extracts from mice 4 or 24 h post-NNK treatment were 30-45% those of control (P<0.05). Conversely, POB adduct repair was 2-3 times higher in liver extracts from NNK treated mice than in controls (4 h, 24 h, P<0.05). NNK treatment also decreased incision of POB adducts by 92% (4 h, P<0.05) in lung and increased incision by 169% (24 h, P<0.05) in liver. NNK decreased immunoreactive levels of the incision protein RPA in lung (P<0.05) 4 h post-treatment but increased immunoreactive lung RPA and XPB after 24 h (P<0.05). In liver, levels of immunoreactive proteins, XPA, XPB and ERCC1 were increased after NNK treatment (24 h, P<0.05). Binding of XPA and XPB from liver extracts to POB adducts increased following NNK treatment, while binding of XPA and XPB from lung decreased (4 h, 24 h). These results suggest that lower incision activity of nucleotide excision repair and NNK-mediated alterations in levels and activities of key incision proteins contribute to the relative susceptibility of mouse lung to NNK-induced carcinogenesis.
Brown
Pamela J
PJ
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Massey
Thomas E
TE
D000818:Animals; D002457:Cell Extracts; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity*; D009687:Nuclear Proteins / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
D002457:Cell Extracts; D018736:DNA Adducts; D009602:Nitrosamines; D009687:Nuclear Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone