Metabolism of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (Nnk) in A/J Mouse Lung And Effect of Cigarette Smoke Exposure on in Vivo Metabolism to Biological Reactive Intermediates

摘要: It has been proposed that the tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) may be involved in causation of human lung cancer (Hecht and Hoffmann, 1988), but direct evidence for involvement NNK is lacking Tricker, 1999). In A/J mouse tumor model, a single intraperitoneal (i.p.) injection 10 μmole [2.07 mg] NNK/mouse results 7–12 tumors per after 16 weeks et al., 1989). The initial events NNK-induced tumorigenesis are believed to metabolism biological reactive intermediates (BRI) with potential react (via methylation DNA) produce O6-methylguanine (O6MeG), GC→AT transitional mispairing, subsequent activation K-ras proto-oncogene (Ronai 1993). α-Hydroxylation methylene carbon atoms adjacent N-nitroso group NNAL yields unstable BM which spontaneously decompose methanediazohydroxide DNA 7-methylguanine (7-MeG), O4-methylthymidine (O4MeT) O6MeG adducts. methyl pyridyloxobutylate DNA, while α-methyl hydroxylation not known result adduct formation. Other metabolic transformations represent detoxification pathways NNAL.