Use of precision-cut tissue slices in organ culture to study metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by hamster lung, liver and kidney

Toxicology. 2000 Apr 3;144(1-3):83-91. doi: 10.1016/s0300-483x(99)00193-6.


The pharmacokinetics of in vitro metabolism of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; concentration range 0.03-250 microM) and its proximal metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; 0.04-250 microM), were determined in Syrian golden hamster liver, lung, and kidney tissue slices in organ culture under identical experimental conditions. In the lung, a target organ for NNK animal carcinogenesis, total NNK metabolism was relatively low (maximum 23%) and oxidative metabolism by alpha-hydroxylation to DNA-reactive intermediates accounted for 13-31% of metabolism. The liver, a non-target organ for NNK carcinogenesis, showed the highest capacity to metabolise NNK (total metabolism 80%), and alpha-hydroxylation accounted for 12-25% of metabolism. The kidney, another non-target organ, also showed a low capacity for NNK metabolism (maximum 32%) and alpha-hydroxylation accounted for <3% of metabolism. Detoxification of NNK by pyridyl N-oxidation was similar in lung (5-22%) and liver (5-23%), and negligible in kidney (<2%), while carbonyl reduction of NNK to NNAL was greatest in the kidney (95-100%), followed by liver (59-79%) and lung (47-81%). NNAL is devoid of biological activity in the hamster and total metabolism was about tenfold lower than that of NNK in all tissues (<13% liver; <4% lung and kidney). In the liver, alpha-hydroxylation was the predominant pathway of NNAL metabolism at almost all concentrations (31-68% of total metabolism), whereas N-oxidation prevailed in the kidney (47-68%). In the lung, a concentration dependent decrease in the relative amount of alpha-hydroxylation (23-72%) with increasing NNAL concentrations occurred at the expense of N-oxidation (25-72%). Little or no metabolism of NNAL back to NNK was evident in any tissue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / metabolism*
  • Chromatography, High Pressure Liquid
  • Cricetinae
  • Female
  • Kidney / enzymology
  • Kidney / metabolism*
  • Kinetics
  • L-Lactate Dehydrogenase / metabolism
  • Liver / enzymology
  • Liver / metabolism*
  • Lung / enzymology
  • Lung / metabolism*
  • Mesocricetus
  • Microtomy / methods*
  • Nitrosamines / metabolism*
  • Organ Culture Techniques / methods*
  • Potassium / metabolism


  • Carcinogens
  • Nitrosamines
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • L-Lactate Dehydrogenase
  • 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol
  • Potassium