Metabolism of the tobacco specific nitrosamines, N'-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.
The metabolism, in the F-344 rat, of the tobacco-specific carcinogens, N'-nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was studied. NNN was hydroxylated at each position of the pyrrolidine ring; 2'-hydroxylation gave 4-hydroxy-1-(3-pyridyl)-1-butanone in vitro and the corresponding acid in vivo, 3'-hydroxylation gave 3'-hydroxyNNN, 4'-hydroxylation gave 4'-hydroxy-NNN and 5'-hydroxylation gave 4-hydroxy-4-(3-pyridyl)butanal (in vitro) and 4-hydroxy-4-(3-pyridyl) butanoic acid (in vivo). The principle ring hydroxylation in the untreated F-344 rat was 5'-hydroxylation. Pyridine N-oxidation was also observed, giving NNN-1-N-oxide as a major metabolite. The principle urinary metabolites of NNN were formed by 5'-hydroxylation and pyridine-N-oxidation. For NNK, a major process was reduction of the carbonyl to give 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanol. alpha-Hydroxylation of both the N-methyl and N-methylene groups was also observed, as was formation of NNK-N-oxide in vitro and in vivo.
D000818:Animals; D001711:Biotransformation; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D009538:Nicotine / Q000031:analogs & derivatives* / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D010947:Plants, Toxic; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D014026:Nicotiana / Q000032:analysis*
D009602:Nitrosamines; D011725:Pyridines; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C008655:N'-nitrosonornicotine