Nachiappan V, Mufti S I, Chakravarti A, Eskelson C D, Rajasekharan R
Department of Pharmacology, University of Arizona, Tucson 85721.
Alcohol Alcohol. 1994 Sep;29(5):565-74.
Male Fischer-344 rats were treated, by gavage, with a total dose of 40 mmol/kg of N'-nitrosonornicotine (NNN) or 20 mmol/kg of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), three times a week for 4 weeks. One week afterwards the rats were fed an isocaloric liquid diet containing 7% (v/v) ethanol and continued on this diet until killed. Cumulative ethane exhaled by a rat by 180 min was measured at 54 weeks of the start of the study and was found to increase significantly (P < 0.001) with either NNN or NNK treatment but more so when followed by ethanol consumption. Other indices of lipid peroxidation, cholesterol and phospholipids were measured in the lipid extracts from the liver, esophagus and lungs at 55 weeks. Ethanol consumption increased the amount of cholesterol and phospholipids per g of tissue in naïve or NNN- and NNK-treated rats. All peroxidative indices measured, i.e. malondialdehyde (MDA), diene- and triene-conjugates and lipid fluorescence, were significantly increased in the liver, the main metabolic and peroxidative site, with ethanol consumption in rats whether they were treated with NNN or NNK or remained untreated. Overall, the indices of lipid peroxidation also showed an increase in other tissues, but the results differed with different indices. The differences in indices may be due to differences in lipid peroxidation products measured or to differences in their rates of production and degradation or conversion to other products. However, the largest increases in indices were seen with ethanol consumption by either NNN- or NNK-treated rats. Incidence of tumors in the tissues was also assessed and showed about a two-fold increase with ethanol consumption in the tumors of esophagus, oral cavity, lungs and liver induced by either NNN or NNK. Ethanol also caused an increase in the mean frequency and mean size of the tumors induced. The results suggest that ethanol-related promotion of NNN- and NNK-induced tumors may result from increased lipid peroxidation in the target tissue.
雄性Fischer-344大鼠通过灌胃给予总剂量为40 mmol/kg的N'-亚硝基降烟碱（NNN）或20 mmol/kg的4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK），每周3次，共4周。1周后，给大鼠喂食含7%（v/v）乙醇的等热量液体饮食，并持续该饮食直至处死。在研究开始54周时测量大鼠180分钟内呼出的累积乙烷量，发现无论是NNN还是NNK处理，该量均显著增加（P < 0.001），但在随后摄入乙醇时增加得更多。在55周时，测量了肝脏、食管和肺脂质提取物中的其他脂质过氧化指标、胆固醇和磷脂。乙醇摄入增加了未处理或经NNN和NNK处理大鼠每克组织中的胆固醇和磷脂含量。在肝脏这个主要的代谢和过氧化部位，无论大鼠是经NNN或NNK处理还是未处理，所有测量的过氧化指标，即丙二醛（MDA）、二烯和三烯共轭物以及脂质荧光，都因乙醇摄入而显著增加。总体而言，脂质过氧化指标在其他组织中也有所增加，但不同指标的结果有所不同。指标差异可能是由于所测量的脂质过氧化产物不同，或者是由于它们的产生、降解速率或转化为其他产物的速率不同。然而，无论是经NNN还是NNK处理的大鼠，在摄入乙醇时指标增加幅度最大。还评估了组织中的肿瘤发生率，结果显示，由NNN或NNK诱导的食管、口腔、肺和肝脏肿瘤，在摄入乙醇时发生率增加了约两倍。乙醇还导致诱导肿瘤的平均频率和平均大小增加。结果表明，乙醇相关促进NNN和NNK诱导肿瘤的发生可能是由于靶组织中脂质过氧化增加所致。
