In vitro and in vivo modulation of the bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in hamster lung tissues.
The metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by hamster lung explants was studied. The three major metabolic pathways were alpha-C-hydroxylation (activation), pyridine N-oxidation (deactivation) and carbonyl reduction. alpha-C-Hydroxylation and pyridine N-oxidation were linear with time (0.5-5 h) and number of explants per dish (3-10). Addition of [2-(diethylamino)ethyl 2,2-diphenylpentenoate] hydrochloride (SKF-525A) to the culture medium reduced alpha-C-hydroxylation and pyridine N-oxidation. alpha-C-Hydroxylation was enhanced by treatment of the hamsters with the two cytochrome P-450 inducers, phenobarbital and 3-methylcholanthrene. These results suggest that cytochrome P-450 monooxygenases are involved in the activation of NNK by alpha-C-hydroxylation. Three groups of hamsters were fed a control diet or diet supplemented with 2% 2(3)-tert-butyl 4-hydroxyanisole (2(3)-BHA) or given a 0.002% solution of (S)-nicotine to drink for two weeks. Lung explants were then cultured with NNK in vitro. Treatment with 2(3)-BHA and (S)-nicotine induced the alpha-C-hydroxylation pathways. Pyridine N-oxidation was increased by (S)-nicotine treatment. These results indicate that dietary factors and tobacco smoke components can modulate the metabolism of NNK.
Charest
M
M
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Rossignol
G
G
Castonguay
A
A
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D008748:Methylcholanthrene / Q000494:pharmacology*; D009602:Nitrosamines / Q000378:metabolism*; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D012016:Reference Values
D002273:Carcinogens; D009602:Nitrosamines; D011506:Proteins; D008748:Methylcholanthrene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D011335:Proadifen; D010634:Phenobarbital