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Carcinogenesis, Vol. 20, No. 8, 1577-1582, August 1999
© 1999 Oxford University Press

Carcinogenesis

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. Hecht1

University of Minnesota Cancer Center, Box 806 Mayo, 420 Delaware Street SE, Minneapolis, MN 55455, USA

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] ß-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 {alpha}-hydroxylation, to NNAL-N-oxide, to adenosine dinucleotide phosphate adducts and to NNK. In lung microsomes, metabolic activation by {alpha}-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.

Abbreviations: 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-[{alpha}-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] ß-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

1 To whom correspondence should be addressed Email: hecht002{at}tc.umn.edu


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