4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen found specifically in tobacco products. It has been shown to be a lung-specific carcinogen in rodents, and may play a critical role in the formation of lung cancer in smokers. One of the enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK, may be important to the selective pulmonary carcinogenicity of NNK. The objective of the current research was to better characterize the pulmonary metabolism of NNK, (S)-NNAL, and (R)-NNAL using the isolated perfused rat lung (IPRL) system to elucidate the mechanisms behind the lung-specific nature of NNK. This research examined metabolite formation, distribution of the metabolites between the perfusate and tissue, the formation of individual DNA adducts in the tissue, and the effects of concentration and the chemopreventive agent PEITC. The results showed that NNK was readily metabolized and DNA adducts were detected in the tissue at the end of the 180 min perfusions. Both an increase in NNK concentration and the co-administration of PEITC were shown to inhibit NNK metabolism. PEITC was also shown to significantly reduce the formation of DNA adducts. The results obtained for the NNK perfusions were in agreement with previously published results. (S)-NNAL and (R)-NNAL were not metabolized as extensively by the lung as NNK. The metabolism of the two enantiomers was similar, which was in contrast to previous in vitro and in vivo results. The only observed difference between the two enantiomers was the formation of low levels of a pyridyloxobutyl (POB)-DNA adduct in the (S)-NNAL perfusions, which indicated reoxidation to NNK. The unexpected results for the NNAL enantiomers may be a result of diffusional barriers to the preformed metabolites that do not exist when the enantiomers are formed from NNK in the tissue. This work showed that the IPRL system was a valid system for examining the pulmonary metabolism of NNK and the formation of DNA adducts, but it may have some limitations for more polar compounds that cannot penetrate the diffusional barriers of the lung and the cells to gain access to the enzymatic sites responsible for metabolism.
University of Minnesota Ph.D. dissertation. August 2010. Major: Pharmaceutics. Advisor:Dr. Cheryl L. Zimmerman, Ph.D. 1 computer file (PDF); xv, 141 pages.
Maertens, Laura A..
The metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] and the enantiomers of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol [NNAL] in the isolated perfused rat lung system..
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