Journal Article

Tumorigenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol enantiomers and metabolites in the A/J mouse

Pramod Upadhyaya, Patrick M.J. Kenney, J. Bradley Hochalter, Mingyao Wang and Stephen S. Hecht

in Carcinogenesis

Volume 20, issue 8, pages 1577-1582
Published in print August 1999 | ISSN: 0143-3334
Published online August 1999 | e-ISSN: 1460-2180 | DOI:
Tumorigenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol enantiomers and metabolites in the A/J mouse

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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of the tobacco-specific pulmonary carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), has a chiral center but the tumorigenicity of the NNAL enantiomers has not been previously examined. In this study, we assessed the relative tumorigenic activities in the A/J mouse of NNK, racemic NNAL, (R)-NNAL, (S)-NNAL and several NNAL metabolites, including [4-(methylnitrosamino)-1-(3-pyridyl)but-(S)-1-yl] β-O-D-gluco-siduronic acid [(S)-NNAL-Gluc], 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanol, 5-(3-pyridyl)-2-hydroxytetrahydrofuran, 4-(3-pyridyl)butane-1,4-diol and 2-(3-pyridyl) tetrahydrofuran. We also quantified urinary metabolites of racemic NNAL and its enantiomers and investigated their metabolism with A/J mouse liver and lung microsomes. Groups of female A/J mice were given a single i.p. injection of 20 μmol of each compound and killed 16 weeks later. Based on lung tumor multiplicity, (R)-NNAL (25.6 ± 7.5 lung tumors/mouse) was as tumorigenic as NNK (25.3 ± 9.8) and significantly more tumorigenic than racemic NNAL (12.1 ± 5.6) or (S)-NNAL (8.2 ± 3.3) (P < 0.0001). None of the NNAL metabolites was tumorigenic. The major urinary metabolites of racemic NNAL and the NNAL enantiomers were 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid), NNAL-N-oxide and NNAL-Gluc, in addition to unchanged NNAL. Treatment with (R)-NNAL or (S)-NNAL gave predominantly (R)-hydroxy acid or (S)-hydroxy acid, respectively, as urinary metabolites. While treatment of mice with racemic or (S)-NNAL resulted in urinary excretion of (S)-NNAL-Gluc, treatment with (R)-NNAL gave both (R)-NNAL-Gluc and (S)-NNAL-Gluc in urine, apparently through the metabolic intermediacy of NNK. (S)-NNAL appeared to be a better substrate for glucuronidation than (R)-NNAL in the A/J mouse. Mouse liver and lung microsomes converted NNAL to products of α-hydroxylation, to NNAL-N-oxide, to adenosine dinucleotide phosphate adducts and to NNK. In lung microsomes, metabolic activation by α-hydroxylation of (R)-NNAL was significantly greater than that of (S)-NNAL. The results of this study provide a metabolic basis for the higher tumorigenicity of (R)-NNAL than (S)-NNAL in A/J mouse lung, namely preferential metabolic activation of (R)-NNAL in lung and preferential glucuronidation of (S)-NNAL.

Keywords: diol, 4-(3-pyridyl)butane-1,4-diol; hydroxy acid, 4-hydroxy-4-(3-pyridyl)butanoic acid; lactol, 5-(3-pyridyl)-2-hydroxytetrahydrofuran; LC-MS/MS, liquid chromatography–tandem mass spectrometry; MMPB, methyl 4-[α-methylbenzylcarbamoyl]-4-(3-pyridyl)butanoate; NNAL, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol; NNAL(ADP)+, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol adenosine dinucleotide phosphate; NNAL-Gluc, [4-(methylnitrosamino)-1-(3-pyridyl)but-(S)-1-yl] β-O-d-glucosiduronic acid; NNAL-N-oxide, 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanol; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNK-N-oxide, 4-(methylnitrosamino)-1-(3-pyridyl N-oxide)-1-butanone; pyridyl-THF, 5-(3-pyridyl)tetrahydrofuran; UDPGA, uridine 5′-diphosphoglucoronic acid

Journal Article.  4739 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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