Metabolic a-Hydroxylation of the Tobacco-specific Carcinogen, N'

Chi Hong B. Chen, Stephen Hecht, Dietrich Hoffmann

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The metabolism of the tobacco-specific carcinogen, N'-nitrosonornicotine, was studied in the rat. Emphasis was placed on metabolic a-hydroxylation, which is a likely activation pathway for this compound. Since a-hydroxyni-trosamines are unstable, the hydrolyses of the model compounds 2'-acetoxy-N'-nitrosonornicotine and 5'-acetoxy-N'-nitrosonornicotine were studied to determine the products resulting from decomposition of 2'-hydroxy-N'-nitrosonomicotlne and 5'-hydroxy-AT-nitrosonornicotine. Hydrolysis of 2'-acetoxy-N'-nitrosonornicotlne gave myosmine (50 to 60%) and 4-hydroxy-1-(3-pyridyl)-1-butanone (5 to 10%) as the main products, whereas 5'-acetoxy-N'-nitrosonomicotine yielded predominantly 2-hydroxy-5-(3-pyridyl)tetrahydrofuran (60 to 70%). Hydrolysis of an additional model compound for 2'-hydroxylation, 4-(N-carbeth-oxy-N-nitrosamino)-1-(3-pyridy1)-1-butanone also gave 4-hydroxy-1-<3-py rldyl)-1-butanone (50 to 60%). These results support the intermediacy of electrophilic diazohydroxides and/or carbonium Ions in the decomposition of 2'-hydroxy-N'-nitrosonornicotine and 5'-hydroxy-M'-nitrosonomicotine. These electrophiles may be active forms of N'-nitrosonornicotine since all three model compounds were mutagenic towards Salmonella typhlmurlum TA 100 without enzymatic activation. To demonstrate metabolic a-hydroxylation of N'-nitro-sonornicotine, the products of decomposition of 2'-hydroxy-N'-nitrosonomicotine and 5'-hydroxy-M'-nitrosonornicotine were identified as metabolites. When N'-[2'-14C]nitrosonomicotine was incubated with rat liver microsomes, 02and a reduced nicotinamide adenine dinucleotide phosphate-generating system, 4-hydroxy-1-(3-pyridyl)-1-butanone and 2-hydroxy-5-(3-pyridyptetra-hydrofuran were identified as their 2,4-dinitrophenylhydrazone derivatives. Myosmine was also formed in vitro. When male F-344 rats were given s.c. Injections of N'-[2'-14C]nitrosonomicotine, 73 to 85% of the dose appeared in the 48-hr urine. The major metabolites resulting from a-hydroxylation of N'-nitrosonornicotine in vivo were 4-(3-pyridyl)-4-oxobutyric acid, 4-hydroxy-4-(3-pyridyl)-butyric acid, and 5-(3-pyridyl)tetrahydrofuran-2-one which are metabolic oxidation products of 4-hydroxy-1-(3-pyridyl)-1-butanone and 2-hydroxy-5-(3-pyridyl)tetrahydrofuran.

Original languageEnglish (US)
Pages (from-to)3639-3645
Number of pages7
JournalCancer Research
StatePublished - Nov 1978


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