Metabolism in the F344 rat of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific carcinogen.
The metabolism of the tobacco-specific carcinogen, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was studied in the F344 rat, in which it induces tumors of the nasal cavity, liver, and lung. When NNK was incubated with rat liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system, metabolites resulting from alpha-hydroxylation, carbonyl reduction, and N-oxidation were isolated. alpha-Hydroxylation at the methylene carbon gave 4-oxo-4-(3-pyridyl)butanal, whereas alpha-hydroxylation at the methyl carbon gave myosmine and 4-hydroxyl-1-(3-pyridyl)butan-1-one. The formation of these products involved the intermediacy of electrophilic diazohydroxides or carbonium ions which may be proximate or ultimate carcinogens of NNK. Carbonyl reduction gave 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)butan-1-ol and N-oxidation yielded 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone. When rats were gavaged with NNK, the microsomal products of alpha-hydroxylation were not detected in the 48-hr urine. Compounds which presumably resulted from further oxidation or reduction of these products, 4-oxo-4-(3-pyridyl)butyric acid, 4-hydroxy-4-(3-pyridyl)butyric acid, and 4-hydroxy-1-(3-pyridyl)butan-1-ol, were isolated. 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)butan-1-ol and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl-N-oxide)-1 butanone were also urinary metabolites.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D010947:Plants, Toxic; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344 / Q000378:metabolism*; D011919:Rats, Inbred Strains / Q000378:metabolism*; D014026:Nicotiana
D002273:Carcinogens; D009602:Nitrosamines; D011725:Pyridines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone