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Metabolic -Hydroxylation of the Tobacco-specific Carcinogen, N'-Nitrosonornicotine¹

Division of Environmental Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595

The metabolism of the tobacco-specific carcinogen, N'-nitrosonornicotine, was studied in the rat. Emphasis was placed on metabolic -hydroxylation, which is a likely activation pathway for this compound. Since -hydroxynitrosamines are unstable, the hydrolyses of the model compounds 2'-acetoxy-N'-nitrosonomicotine and 5'-acetoxy-N'-nitrosonomicotine were studied to determine the products resulting from decomposition of 2'-hydroxy-N'-nitrosonornicotine and 5'-hydroxy-N'-nitrosonornicotine. Hydrolysis of 2'-acetoxy-N'-nitrosonornicotine gave myosmine (50 to 60%) and 4-hydroxy-1-(3-pyridyl)-1-butanone (5 to 10%) as the main products, whereas 5'-acetoxy-N'-nitrosonornicotine yielded predominantly 2-hydroxy-5-(3-pyridyl)tetrahydrofuran (60 to 70%). Hydrolysis of an additional model compound for 2'-hydroxylation, 4-(N-carbethoxy-N-nitrosamino)-1-(3-pyridyl)-1-butanone also gave 4-hydroxy-1-(3-pyridyl)-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-N'-nitrosonornicotine. These electrophiles may be active forms of N'-nitrosonornicotine since all three model compounds were mutagenic towards Salmonella typhimurium TA 100 without enzymatic activation.

To demonstrate metabolic -hydroxylation of N'-nitrosonornicotine, the products of decomposition of 2'-hydroxy-N'-nitrosonornicotine and 5'-hydroxy-N'-nitrosonornicotine were identified as metabolites. When N'-[2'-¹⁴C]nitrosonornicotine was incubated with rat liver microsomes, O₂, and a reduced nicotinamide adenine dinucleotide phosphate-generating system, 4-hydroxy-1-(3-pyridyl)-1-butanone and 2-hydroxy-5-(3-pyridyl)tetrahydrofuran 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]nitrosonornicotine, 73 to 85% of the dose appeared in the 48-hr urine. The major metabolites resulting from -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.

¹ This study was supported by Grant CA-21393 from the National Cancer Institute. This is Paper 11 of the series, "A Study of Chemical Carcinogenesis."

² To whom requests for reprints should be addressed.

³ Recipient of National Cancer Institute Research Career Development Award 5KO4CA00124.

Received 5/ 5/78. Accepted 7/27/78.