Lamoureux J, Castonguay A
Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada.
Carcinogenesis. 1997 Oct;18(10):1979-84. doi: 10.1093/carcin/18.10.1979.
The N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in tobacco and tobacco smoke. Carbonyl reduction, alpha-carbon hydroxylation (activation) and N-oxidation of the pyridyl ring (detoxification) are the three main pathways of metabolism of NNK. In this study, metabolism of NNK was studied with lung and liver microsomes from F344 rats, Syrian golden hamsters and pigs and cloned flavin-containing monooxygenases (FMOs) from human and rabbit liver. Thermal inactivation at 45 degrees C for 2 min reduced FMO S-oxygenating activity but did not affect N-oxidation of NNK, leading to the conclusion that FMOs are not implicated in the detoxification of NNK. Detoxification of NNK was not increased by n-octylamine or by incubation at pH 8.4, supporting the conclusion that FMOs are not involved in the metabolism of NNK. SKF-525A (1 mM) significantly reduced N-oxidation and alpha-carbon hydroxylation, suggesting that these two pathways were catalyzed by cytochromes P450. Metabolism of NNK was lower with lung microsomes than with liver microsomes. Inhibition of metabolism of NNK by SKF-525A was also observed with rat lung microsomes, leading to the conclusion that cytochromes P450 are involved in pulmonary metabolism of NNK. Cloned FMOs did not metabolize NNK. In conclusion, cytochromes P450 rather than FMOs are involved in N-oxidation of NNK. The high capacity of hamster liver microsomes to activate NNK does not correlate with the resistance of this tissue to NNK-induced hepatocarcinogenesis.
N-亚硝基胺4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮(NNK)是烟草和烟草烟雾中存在的一种强效肺致癌物。羰基还原、α-碳羟基化(活化)和吡啶环的N-氧化(解毒)是NNK的三种主要代谢途径。在本研究中，利用F344大鼠、叙利亚金黄地鼠和猪的肺和肝微粒体以及人肝和兔肝克隆的含黄素单加氧酶(FMOs)研究了NNK的代谢。45℃热灭活2分钟降低了FMO的S-氧化活性，但不影响NNK的N-氧化，得出FMOs与NNK解毒无关的结论。正辛胺或在pH 8.4下孵育均未增加NNK的解毒作用，支持FMOs不参与NNK代谢的结论。SKF-525A(1 mM)显著降低了N-氧化和α-碳羟基化，表明这两条途径由细胞色素P450催化。肺微粒体对NNK的代谢低于肝微粒体。在大鼠肺微粒体中也观察到SKF-525A对NNK代谢的抑制作用，得出细胞色素P450参与NNK肺代谢的结论。克隆的FMOs不代谢NNK。总之，细胞色素P450而非FMOs参与NNK的N-氧化。仓鼠肝微粒体激活NNK的高能力与该组织对NNK诱导的肝癌发生的抗性无关。
