Author(s): Richter E, Friesenegger S, Engl J, Tricker AR, Richter E, Friesenegger S, Engl J, Tricker AR
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Abstract 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.
This article was published in Toxicology
and referenced in Journal of Cancer Science & Therapy