Jorquera R, Castonguay A, Schuller H M
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada.
Drug Metab Dispos. 1993 Mar-Apr;21(2):318-24.
The tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in Syrian golden hamsters exposed pre- or postnatally to NNK. NNK requires metabolic activation, mainly by the cytochrome P-450 monooxygenase system, to exert its carcinogenic activity. Along with carcinogens, tobacco smoke contains other biologically active substances such as enzyme inducers and inhibitors. In this study, we have investigated the effects of tobacco smoke condensate (TSC) on microsomal metabolism of NNK in hamsters. TSC was instilled intratracheally to non-pregnant and pregnant hamsters on days 12, 13, and 14 of gestation. Following euthanasia on day 15 of gestation, liver and lung microsomes from adult and fetal hamsters were prepared, and the metabolism of NNK was analyzed by HPLC. Although TSC tended to increase the formation of some alpha-carbon hydroxylation metabolites with liver microsomes from adult hamsters, none of the metabolic pathways of NNK showed a statistically significant increase or decrease caused by TSC exposure. Similarly, no significant alterations of NNK metabolism were observed with lung microsomes from TSC-treated adult hamsters, as well as with liver or lung microsomes from fetal hamsters exposed in utero to TSC. As shown by Western blotting analyses, the protein levels of the P-450 enzymes most likely involved in NNK metabolism (i.e. P-450IIB1 and P-450IIE1) remained almost unchanged in liver or lung microsomes from TSC-exposed hamsters. Interestingly, the P-450IIB1 protein content was increased in lung microsomes from TSC-treated pregnant hamsters, an effect likely related to the altered hormonal status of these animals.(ABSTRACT TRUNCATED AT 250 WORDS)
烟草特有的N-亚硝胺4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)，对于出生前或出生后接触NNK的叙利亚金仓鼠来说，是一种强效致癌物。NNK需要代谢激活，主要通过细胞色素P-450单加氧酶系统来发挥其致癌活性。除了致癌物外，烟草烟雾还含有其他生物活性物质，如酶诱导剂和抑制剂。在本研究中，我们调查了烟草烟雾浓缩物(TSC)对仓鼠体内NNK微粒体代谢的影响。在妊娠第12、13和14天，将TSC经气管内注入未怀孕和怀孕的仓鼠体内。在妊娠第15天实施安乐死后，制备成年和胎儿仓鼠的肝脏和肺微粒体，并通过高效液相色谱法分析NNK的代谢情况。尽管TSC倾向于增加成年仓鼠肝脏微粒体中一些α-碳羟基化代谢物的形成，但NNK的任何代谢途径均未显示出因接触TSC而导致的统计学上显著的增加或减少。同样，在经TSC处理的成年仓鼠的肺微粒体中，以及在子宫内接触TSC的胎儿仓鼠的肝脏或肺微粒体中，均未观察到NNK代谢的显著改变。蛋白质印迹分析表明，最有可能参与NNK代谢的P-450酶(即P-450IIB1和P-450IIE1)的蛋白水平在接触TSC的仓鼠的肝脏或肺微粒体中几乎保持不变。有趣的是，在经TSC处理的怀孕仓鼠的肺微粒体中，P-450IIB1蛋白含量增加，这一效应可能与这些动物激素状态的改变有关。(摘要截短于250字)
