title: Effects of dietary 1,4-phenylenebis(methylene)selenocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA adduct formation in lung and liver of A/J mice and F344 rats.
abstract: 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) was tested for its ability to inhibit DNA adduct formation induced by the tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the liver and lung of A/J mice and F344 rats. Dietary p-XSC, providing a dose of 5 p.p.m. selenium, significantly inhibited the formation of 7-methylguanine (7-mGua) induced by a single i.p. injection of 10 mumol of NNK(12.8% inhibition at 4 h and 19.9% at 96 h) and O6-methylguanine (O6-mGua) (16.5% at 4 h and 34.8% at 96 h) in the liver of A/J mice. Dietary supplements of p-XSC providing 15 p.p.m. of selenium reduced the levels of 7-mGua by 17.3% (4 h) and 33.6% (96 h). The formation of O6-mGua was inhibited by 69.5% (4th) and 73.8 (96h). In A/J mouse lung DNA the most significant reduction was observed in levels of O6-mGua. Dietary p-XSC at 5 p.p.m. as selenium inhibited the formation of this adduct by 73.1% (4 h). Ninety-six hours after NNK injection, and at both time points with p-XSC providing 15 p.p.m. selenium, O6-mGua was not detected. Although levels of 7- mGua in mouse lung DNA were also reduced, this was significant only 4 h after carcinogen administration. In general, selenite at a5 p.p.m. as selenium had no significant effect on the levels of these lesions; however, it inhibited O6-mGua in the liver only 4 h after NNK administration. These effects may explain why there is chemopreventive activity for p-XSC, but not for selenite, in NNK-induced lung carcinogenesis in A/J mice. Moreover, these findings raised our interest in determining the potential chemopreventive activity of p-XSC against NNK-induced lung adenocarcinomas in male F344 rats by first determining its effects on NNK-induced DNA methylation in the lungs of rats. Diet supplemented with 10 p.p.m. selenium as p-XSC did indeed inhibit the formation of adducts in pulmonary DNA of F344 rats treated with four consecutive injections of 81 mg/kg of NNK. Statistically significant inhibition of O6-mGua formation was observed 4 h after carcinogen treatment in both pulmonary (49.1% inhibition) and hepatic (39.8%) DNA. Statistically significant inhibition of 7-mGua formation was also measured in lung DNA isolated 24 h after the last NNK injection (45.0%) and in liver DNA 4 h after carcinogen treatment (31.8%). These results suggest that p-XSC would also inhibit induction of lung adenocarcinoma in male F344 rats by NNK.
authors.affiliation: American Health Foundation, New York, NY 10595, USA.
authors.forename: B
authors.initials: B
authors.lastname: Prokopczyk
authors.forename: J E
authors.initials: JE
authors.lastname: Cox
authors.forename: P
authors.initials: P
authors.lastname: Upadhyaya
authors.forename: S
authors.initials: S
authors.lastname: Amin
authors.forename: D
authors.initials: D
authors.lastname: Desai
authors.forename: D
authors.initials: D
authors.lastname: Hoffmann
authors.forename: K
authors.initials: K
authors.lastname: el-Bayoumy
mesh_terms: D000230:Adenocarcinoma / Q000517:prevention & control; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts; D004032:Diet; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control; D008297:Male; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D009602:Nitrosamines; D016566:Organoselenium Compounds; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C074153:1,4-phenylenebis(methylene)selenocyanate