Characterization of a glucuronide metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk) and its dose-dependent excretion in the urine of mice and rats

Mark A. Morse, Karin I. Eklind, Mary Toussaint, Shantu Amin, Fung Lung Chung

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Abstract

Following analysis by reversed-phase HPLC, a previously uncharacterized metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was found in the urine of A/J mice treated with NNK. Treatment with β-glucuronidase converted the metabolite to a peak that co-eluted with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Treatment with sulfatase or β-glucuronidase plus saccharic acid 1,4-lactone did not change the retention time of the metabolite. These data suggested that the unknown metabolite was a glucuronic acid conjugate of NNAL. Upon isolation and purification of larger quantities of the metabolite from the urine of A/J mice, CD-1 mice and F344 rats, 1H and 13C NMR and MS confirmed that the unknown metabolite was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butyl β-D-glucopyranosiduronic acid (NNAL Glu). To determine the quantitative relationship between NNK dose and NNAL Glu production and to compare the importance of glucuronidation relative to other metabolic pathways, [5-3H]NNK was administered to F344 rats and A/J mice at doses of 500-0.005 μmol/kg. At 500 μNNAL Glu accounted for 22% of the total urinary excretion of NNK in A/J mice, and for 8% in F344 rats 48 h after dosing. The proportions of excreted glucuronide and NNAL decreased with diminishing doses of NMK, yielding undetectable levels of each metabolite in both mice and rats at a dose of 0.005 μmol/kg NNK. Since substantial amounts of metabolites formed via α-hydroxylatlon and N-oxidation pathways were observed at the lower doses of NNK, these data demonstrate that NNAL glucuronidation is a quantitatively unimportant metabolic pathway at low doses of NNK.

Original languageEnglish (US)
Pages (from-to)1819-1823
Number of pages5
JournalCarcinogenesis
Volume11
Issue number10
DOIs
StatePublished - Oct 1 1990

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Glucuronides
Urine
Inbred F344 Rats
Glucuronidase
Metabolic Networks and Pathways
Sulfatases
Glucuronic Acid
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
High Pressure Liquid Chromatography
Acids

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

@article{3f918655877c4497b7960c464b26d4ed,
title = "Characterization of a glucuronide metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk) and its dose-dependent excretion in the urine of mice and rats",
abstract = "Following analysis by reversed-phase HPLC, a previously uncharacterized metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was found in the urine of A/J mice treated with NNK. Treatment with β-glucuronidase converted the metabolite to a peak that co-eluted with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Treatment with sulfatase or β-glucuronidase plus saccharic acid 1,4-lactone did not change the retention time of the metabolite. These data suggested that the unknown metabolite was a glucuronic acid conjugate of NNAL. Upon isolation and purification of larger quantities of the metabolite from the urine of A/J mice, CD-1 mice and F344 rats, 1H and 13C NMR and MS confirmed that the unknown metabolite was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butyl β-D-glucopyranosiduronic acid (NNAL Glu). To determine the quantitative relationship between NNK dose and NNAL Glu production and to compare the importance of glucuronidation relative to other metabolic pathways, [5-3H]NNK was administered to F344 rats and A/J mice at doses of 500-0.005 μmol/kg. At 500 μNNAL Glu accounted for 22{\%} of the total urinary excretion of NNK in A/J mice, and for 8{\%} in F344 rats 48 h after dosing. The proportions of excreted glucuronide and NNAL decreased with diminishing doses of NMK, yielding undetectable levels of each metabolite in both mice and rats at a dose of 0.005 μmol/kg NNK. Since substantial amounts of metabolites formed via α-hydroxylatlon and N-oxidation pathways were observed at the lower doses of NNK, these data demonstrate that NNAL glucuronidation is a quantitatively unimportant metabolic pathway at low doses of NNK.",
author = "Morse, {Mark A.} and Eklind, {Karin I.} and Mary Toussaint and Shantu Amin and Chung, {Fung Lung}",
year = "1990",
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pages = "1819--1823",
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Characterization of a glucuronide metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk) and its dose-dependent excretion in the urine of mice and rats. / Morse, Mark A.; Eklind, Karin I.; Toussaint, Mary; Amin, Shantu; Chung, Fung Lung.

In: Carcinogenesis, Vol. 11, No. 10, 01.10.1990, p. 1819-1823.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Characterization of a glucuronide metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk) and its dose-dependent excretion in the urine of mice and rats

AU - Morse, Mark A.

AU - Eklind, Karin I.

AU - Toussaint, Mary

AU - Amin, Shantu

AU - Chung, Fung Lung

PY - 1990/10/1

Y1 - 1990/10/1

N2 - Following analysis by reversed-phase HPLC, a previously uncharacterized metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was found in the urine of A/J mice treated with NNK. Treatment with β-glucuronidase converted the metabolite to a peak that co-eluted with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Treatment with sulfatase or β-glucuronidase plus saccharic acid 1,4-lactone did not change the retention time of the metabolite. These data suggested that the unknown metabolite was a glucuronic acid conjugate of NNAL. Upon isolation and purification of larger quantities of the metabolite from the urine of A/J mice, CD-1 mice and F344 rats, 1H and 13C NMR and MS confirmed that the unknown metabolite was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butyl β-D-glucopyranosiduronic acid (NNAL Glu). To determine the quantitative relationship between NNK dose and NNAL Glu production and to compare the importance of glucuronidation relative to other metabolic pathways, [5-3H]NNK was administered to F344 rats and A/J mice at doses of 500-0.005 μmol/kg. At 500 μNNAL Glu accounted for 22% of the total urinary excretion of NNK in A/J mice, and for 8% in F344 rats 48 h after dosing. The proportions of excreted glucuronide and NNAL decreased with diminishing doses of NMK, yielding undetectable levels of each metabolite in both mice and rats at a dose of 0.005 μmol/kg NNK. Since substantial amounts of metabolites formed via α-hydroxylatlon and N-oxidation pathways were observed at the lower doses of NNK, these data demonstrate that NNAL glucuronidation is a quantitatively unimportant metabolic pathway at low doses of NNK.

AB - Following analysis by reversed-phase HPLC, a previously uncharacterized metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was found in the urine of A/J mice treated with NNK. Treatment with β-glucuronidase converted the metabolite to a peak that co-eluted with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Treatment with sulfatase or β-glucuronidase plus saccharic acid 1,4-lactone did not change the retention time of the metabolite. These data suggested that the unknown metabolite was a glucuronic acid conjugate of NNAL. Upon isolation and purification of larger quantities of the metabolite from the urine of A/J mice, CD-1 mice and F344 rats, 1H and 13C NMR and MS confirmed that the unknown metabolite was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butyl β-D-glucopyranosiduronic acid (NNAL Glu). To determine the quantitative relationship between NNK dose and NNAL Glu production and to compare the importance of glucuronidation relative to other metabolic pathways, [5-3H]NNK was administered to F344 rats and A/J mice at doses of 500-0.005 μmol/kg. At 500 μNNAL Glu accounted for 22% of the total urinary excretion of NNK in A/J mice, and for 8% in F344 rats 48 h after dosing. The proportions of excreted glucuronide and NNAL decreased with diminishing doses of NMK, yielding undetectable levels of each metabolite in both mice and rats at a dose of 0.005 μmol/kg NNK. Since substantial amounts of metabolites formed via α-hydroxylatlon and N-oxidation pathways were observed at the lower doses of NNK, these data demonstrate that NNAL glucuronidation is a quantitatively unimportant metabolic pathway at low doses of NNK.

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