Ketonitrosamines as metabolites of methyl-N-amylnitrosamine (MNAN) and its hydroxy derivatives in the rat

Sidney S. Mirvish, Moheb Makary, Phillip Issenberg, Ashok Deshpande, Chuan Ji, Terence A Lawson, David M. Badcock, Samuel Rosinsky

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Abstract

In a previous study of the metabolism of methyl-N-amylnitrosamine (MNAN) in the rat, 2- to 5-hydroxy-MNAN (HOMNAN) were provisionally identified as metabolites and the identity of 4-HO-MNAN was confirmed by mass spectrometry. We now describe syntheses and mass and other spectra for 2- to 5-oxo-MNAN. Two previously unidentified MNAN metabolites were shown to be 3- and 4oxo-MNAN. In addition to 4-HO-MNAN, we confirmed 3-HO-, 4oxo- and (less certainly) 2-HO-MNAN as urinary MNAN metabolites by GLC-MS of HPLC fractions. Analysis with and without β-glucuronidase treatment showed that the urinary HO-MNANs occurred as their β-glucuronides. MNAN (25 mg/kg injected i.p.) had a blood half-life of 21 min in adult male rats. The blood also contained 4-HO- and 4oxo-MNAN, which showed maximum levels that were 13 and 26% respectively of that for MNAN, and were cleared more slowly than MNAN. On incubation for 3 h with MNAN, rat esophagus produced 3- and 4-oxo-MNAN in yields that were 5% of those for the corresponding HO-MNANs. For MNAN metabolism, the 4-oxo-/4-HO-MNAN ratio of metabolites was 5% for adult rat liver and was 22% for adult hamster liver and 9-day-old rat liver. On incubation with 4-HO-MNAN for 3 h, oxidation to 4oxo-MNAN was 16-25% for adult hamster or 9-dayold rat liver slices and for adult hamster liver homogenate. Homogenate activity was concentrated in the microsomal fraction, for which NAD was a more effective co-factor than NADP. A bacterial alcohol dehydrogenase oxidized 4-HO- to 4-oxo-MNAN in 38% yield/3 h. None of these preparations oxidized 2-HO- to 2-oxo-MNAN. It was concluded that 3- and 4-oxo-MNAN were metabolites of MNAN, apparently (for 4-oxo-MNAN) via HO-MNAN oxidation by a microsomal NAD-dependent enzyme, that 4-HO- and 4-oxo-MNAN formation was a major route of MNAN metabolism, and that 4-oxo-MNAN might play a role in MNAN carcinogenesis.

Original languageEnglish (US)
Pages (from-to)2209-2214
Number of pages6
JournalCarcinogenesis
Volume10
Issue number12
DOIs
StatePublished - Dec 1 1989

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Cricetinae
Liver
NAD
Glucuronidase
Glucuronides
NADP
Esophagus
Half-Life
Mass Spectrometry
Carcinogenesis
High Pressure Liquid Chromatography
Enzymes
alcohol dehydrogenase IV

ASJC Scopus subject areas

  • Cancer Research

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Mirvish, S. S., Makary, M., Issenberg, P., Deshpande, A., Ji, C., Lawson, T. A., ... Rosinsky, S. (1989). Ketonitrosamines as metabolites of methyl-N-amylnitrosamine (MNAN) and its hydroxy derivatives in the rat. Carcinogenesis, 10(12), 2209-2214. https://doi.org/10.1093/carcin/10.12.2209

Ketonitrosamines as metabolites of methyl-N-amylnitrosamine (MNAN) and its hydroxy derivatives in the rat. / Mirvish, Sidney S.; Makary, Moheb; Issenberg, Phillip; Deshpande, Ashok; Ji, Chuan; Lawson, Terence A; Badcock, David M.; Rosinsky, Samuel.

In: Carcinogenesis, Vol. 10, No. 12, 01.12.1989, p. 2209-2214.

Research output: Contribution to journalArticle

Mirvish, SS, Makary, M, Issenberg, P, Deshpande, A, Ji, C, Lawson, TA, Badcock, DM & Rosinsky, S 1989, 'Ketonitrosamines as metabolites of methyl-N-amylnitrosamine (MNAN) and its hydroxy derivatives in the rat', Carcinogenesis, vol. 10, no. 12, pp. 2209-2214. https://doi.org/10.1093/carcin/10.12.2209
Mirvish, Sidney S. ; Makary, Moheb ; Issenberg, Phillip ; Deshpande, Ashok ; Ji, Chuan ; Lawson, Terence A ; Badcock, David M. ; Rosinsky, Samuel. / Ketonitrosamines as metabolites of methyl-N-amylnitrosamine (MNAN) and its hydroxy derivatives in the rat. In: Carcinogenesis. 1989 ; Vol. 10, No. 12. pp. 2209-2214.
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abstract = "In a previous study of the metabolism of methyl-N-amylnitrosamine (MNAN) in the rat, 2- to 5-hydroxy-MNAN (HOMNAN) were provisionally identified as metabolites and the identity of 4-HO-MNAN was confirmed by mass spectrometry. We now describe syntheses and mass and other spectra for 2- to 5-oxo-MNAN. Two previously unidentified MNAN metabolites were shown to be 3- and 4oxo-MNAN. In addition to 4-HO-MNAN, we confirmed 3-HO-, 4oxo- and (less certainly) 2-HO-MNAN as urinary MNAN metabolites by GLC-MS of HPLC fractions. Analysis with and without β-glucuronidase treatment showed that the urinary HO-MNANs occurred as their β-glucuronides. MNAN (25 mg/kg injected i.p.) had a blood half-life of 21 min in adult male rats. The blood also contained 4-HO- and 4oxo-MNAN, which showed maximum levels that were 13 and 26{\%} respectively of that for MNAN, and were cleared more slowly than MNAN. On incubation for 3 h with MNAN, rat esophagus produced 3- and 4-oxo-MNAN in yields that were 5{\%} of those for the corresponding HO-MNANs. For MNAN metabolism, the 4-oxo-/4-HO-MNAN ratio of metabolites was 5{\%} for adult rat liver and was 22{\%} for adult hamster liver and 9-day-old rat liver. On incubation with 4-HO-MNAN for 3 h, oxidation to 4oxo-MNAN was 16-25{\%} for adult hamster or 9-dayold rat liver slices and for adult hamster liver homogenate. Homogenate activity was concentrated in the microsomal fraction, for which NAD was a more effective co-factor than NADP. A bacterial alcohol dehydrogenase oxidized 4-HO- to 4-oxo-MNAN in 38{\%} yield/3 h. None of these preparations oxidized 2-HO- to 2-oxo-MNAN. It was concluded that 3- and 4-oxo-MNAN were metabolites of MNAN, apparently (for 4-oxo-MNAN) via HO-MNAN oxidation by a microsomal NAD-dependent enzyme, that 4-HO- and 4-oxo-MNAN formation was a major route of MNAN metabolism, and that 4-oxo-MNAN might play a role in MNAN carcinogenesis.",
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N2 - In a previous study of the metabolism of methyl-N-amylnitrosamine (MNAN) in the rat, 2- to 5-hydroxy-MNAN (HOMNAN) were provisionally identified as metabolites and the identity of 4-HO-MNAN was confirmed by mass spectrometry. We now describe syntheses and mass and other spectra for 2- to 5-oxo-MNAN. Two previously unidentified MNAN metabolites were shown to be 3- and 4oxo-MNAN. In addition to 4-HO-MNAN, we confirmed 3-HO-, 4oxo- and (less certainly) 2-HO-MNAN as urinary MNAN metabolites by GLC-MS of HPLC fractions. Analysis with and without β-glucuronidase treatment showed that the urinary HO-MNANs occurred as their β-glucuronides. MNAN (25 mg/kg injected i.p.) had a blood half-life of 21 min in adult male rats. The blood also contained 4-HO- and 4oxo-MNAN, which showed maximum levels that were 13 and 26% respectively of that for MNAN, and were cleared more slowly than MNAN. On incubation for 3 h with MNAN, rat esophagus produced 3- and 4-oxo-MNAN in yields that were 5% of those for the corresponding HO-MNANs. For MNAN metabolism, the 4-oxo-/4-HO-MNAN ratio of metabolites was 5% for adult rat liver and was 22% for adult hamster liver and 9-day-old rat liver. On incubation with 4-HO-MNAN for 3 h, oxidation to 4oxo-MNAN was 16-25% for adult hamster or 9-dayold rat liver slices and for adult hamster liver homogenate. Homogenate activity was concentrated in the microsomal fraction, for which NAD was a more effective co-factor than NADP. A bacterial alcohol dehydrogenase oxidized 4-HO- to 4-oxo-MNAN in 38% yield/3 h. None of these preparations oxidized 2-HO- to 2-oxo-MNAN. It was concluded that 3- and 4-oxo-MNAN were metabolites of MNAN, apparently (for 4-oxo-MNAN) via HO-MNAN oxidation by a microsomal NAD-dependent enzyme, that 4-HO- and 4-oxo-MNAN formation was a major route of MNAN metabolism, and that 4-oxo-MNAN might play a role in MNAN carcinogenesis.

AB - In a previous study of the metabolism of methyl-N-amylnitrosamine (MNAN) in the rat, 2- to 5-hydroxy-MNAN (HOMNAN) were provisionally identified as metabolites and the identity of 4-HO-MNAN was confirmed by mass spectrometry. We now describe syntheses and mass and other spectra for 2- to 5-oxo-MNAN. Two previously unidentified MNAN metabolites were shown to be 3- and 4oxo-MNAN. In addition to 4-HO-MNAN, we confirmed 3-HO-, 4oxo- and (less certainly) 2-HO-MNAN as urinary MNAN metabolites by GLC-MS of HPLC fractions. Analysis with and without β-glucuronidase treatment showed that the urinary HO-MNANs occurred as their β-glucuronides. MNAN (25 mg/kg injected i.p.) had a blood half-life of 21 min in adult male rats. The blood also contained 4-HO- and 4oxo-MNAN, which showed maximum levels that were 13 and 26% respectively of that for MNAN, and were cleared more slowly than MNAN. On incubation for 3 h with MNAN, rat esophagus produced 3- and 4-oxo-MNAN in yields that were 5% of those for the corresponding HO-MNANs. For MNAN metabolism, the 4-oxo-/4-HO-MNAN ratio of metabolites was 5% for adult rat liver and was 22% for adult hamster liver and 9-day-old rat liver. On incubation with 4-HO-MNAN for 3 h, oxidation to 4oxo-MNAN was 16-25% for adult hamster or 9-dayold rat liver slices and for adult hamster liver homogenate. Homogenate activity was concentrated in the microsomal fraction, for which NAD was a more effective co-factor than NADP. A bacterial alcohol dehydrogenase oxidized 4-HO- to 4-oxo-MNAN in 38% yield/3 h. None of these preparations oxidized 2-HO- to 2-oxo-MNAN. It was concluded that 3- and 4-oxo-MNAN were metabolites of MNAN, apparently (for 4-oxo-MNAN) via HO-MNAN oxidation by a microsomal NAD-dependent enzyme, that 4-HO- and 4-oxo-MNAN formation was a major route of MNAN metabolism, and that 4-oxo-MNAN might play a role in MNAN carcinogenesis.

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