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.
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.
Richter
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Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians University of Munich, Nussbaumstr. 26, D-80336, Munich, Germany. franky.richter@lrz.uni-muenchen.de
Friesenegger
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Engl
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Tricker
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D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005260:Female; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008647:Mesocricetus; D008867:Microtomy / Q000379:methods*; D009602:Nitrosamines / Q000378:metabolism*; D009924:Organ Culture Techniques / Q000379:methods*; D011188:Potassium / Q000378:metabolism
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D007770:L-Lactate Dehydrogenase; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol; D011188:Potassium