title: Protective effects of vitamin A against the genotoxicity of NNK, a nicotine-derived N-nitrosamine.
abstract: In this investigation, the effect of vitamin A on 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced genotoxic damage in rat liver was studied and correlated with NNK metabolism and DNA single strand breaks (DNA-SSBs). Male adult Fischer rats were fed a vitamin A deficient diet for 8 weeks and then divided into two sub-groups. Rats in group Ia and group Ib were fed vitamin A supplemented and vitamin A deficient diets respectively for an additional 4 weeks. Rats were then treated with a single i.p. injection of NNK (25-100 mg/kg) and subjected to partial hepatectomy 1 week later. After 72 h, liver perfusions were performed for cell preparation. Non-hepatectomized rats were used as controls (group IIa and IIb, consisting of rats fed vitamin A supplemented and deficient diets respectively). In non-hepatectomized rats (groups IIa and IIb), micronucleus (MN) frequencies were not significantly increased. This confirms the importance of cell proliferation for MN formation. In rats fed a vitamin A deficient diet and subjected to partial hepatectomy (group Ib), a significant increase of MN was observed (2.2 +/- 0.3, 5.7 +/- 0.9, 12.8 +/- 3.8 and 21.2 +/- 4.3% for control, 25, 50 and 100 mg NNK/kg body wt respectively). In rats fed a vitamin A supplemented diet (group Ia) we have observed a significant decrease of MN induction, as compared to rats fed a vitamin A deficient diet (group Ib) (2.7 +/- 1.0, 2.9 +/- 0.9, 9.7 +/- 2.7, 14.8 +/- 3.2% for control, 25, 50 and 100 mg NNK/kg body wt respectively). Freshly isolated hepatocytes from rats fed vitamin A deficient and supplemented diets but without NNK treatment in vivo were used to study NNK metabolism and DNA-SSBs. Results showed that hepatocytes isolated from rats fed a vitamin A supplemented diet (group C) metabolized NNK less effectively than hepatocytes isolated from rats fed a vitamin A deficient diet (group B) (NNK metabolism was decreased by 0.5-fold in group C as compared to group B). This inhibition was observed only with the NNK activation pathway, alpha-carbon hydroxylation, but not with a deactivation pathway: pyridine-N-oxidation. DNA-SSBs induced by NNK were also reduced in hepatocytes isolated from rats fed a vitamin A supplemented diet as compared to hepatocytes isolated from rats fed a deficient diet. These reductions were 7.8, 12.4 and 4.5% after 6 h of elution and 9.1, 8.5 and 3.0% after 9 h of elution for 1, 5 and 10 mM NNK respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Alaoui-Jamali
authors.forename: G
authors.initials: G
authors.lastname: Rossignol
authors.forename: A
authors.initials: A
authors.lastname: Castonguay
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014801:Vitamin A / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000378:metabolism
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D014801:Vitamin A; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone