TY - JOUR
T1 - Metabolic a-Hydroxylation of the Tobacco-specific Carcinogen, N'
AU - Chen, Chi Hong B.
AU - Hecht, Stephen
AU - Hoffmann, Dietrich
PY - 1978/11
Y1 - 1978/11
N2 - 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.
AB - 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.
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M3 - Article
C2 - 359127
AN - SCOPUS:0018087170
SN - 0008-5472
VL - 38
SP - 3639
EP - 3645
JO - Cancer Research
JF - Cancer Research
ER -