游离脂肪酸和铁络合物发挥协同毒性并通过线粒体代谢诱导基因突变（英文）  

Complexes of free fatty acids and iron exert synergistic toxicity and induce DNA mutation through mitochondrial metabolism

作　　者：刘曌宇[1] 于海兵[2] Athanasios Vlessidis 刘正湘[1,4] 孔丹莉[2] 姚大纯[1,2,3,5] 

机构地区：[1]华中科技大学同济医学院附属同济医院内科,湖北武汉430030 [2]广东医学院公共卫生学院,广东东莞523808 [3]Lab of Analytical Chemistry,Department of Chemistry,University of Ioannina [4]华中科技大学同济文昌医院,海南文昌571321 [5]Department of Medicine,Albert Einstein College of Medicine

出　　处：《广东医学院学报》2015年第2期123-133,共11页Journal of Guangdong Medical College

基　　金：湖北省自然科学基金项目(No.2014CFB437)

摘　　要：目的由于烟草烟雾中游离脂肪酸可与二价铁形成亲脂性复合物并输送铁到哺乳动物细胞,故其可能是重要的有毒成分。尽管早已发现这种铁负载增加了细胞膜不饱和脂肪酸氧化易感性,但脂肪酸:铁络合物的其他毒性所知甚少。方法利用酿酒酵母研究脂肪酸和铁的协同毒性和突变作用,同时观察了线粒体中脂肪酸介导铁沉积、脂质过氧化和活性氧产生。结果单纯铁和游离脂肪酸对酵母的活性及突变无明显影响,但二者联用有明显毒性。把酵母悬浮液在氮气中孵育可防止这种毒性,表明线粒体代谢生成的活性氧可能参与其中。呼吸缺陷酵母可对抗铁:脂肪酸诱导的毒性,具有增强铁储存能力的CCC1过表达酵母也有类似的保护作用。因维生素E或拉扎洛依(多不饱和脂肪酸过氧化反应抑制剂)可防止其杀伤作用,铁+脂肪酸的细胞毒性作用很可能是由膜多不饱和脂肪酸氧化损伤介导。结论铁:脂肪酸络合物所致铁超负荷的毒性作用可能涉及线粒体代谢。如果酵母中这些结果与吸烟相关的渐进性肺损伤有关,意味着烟草中看似无害的脂肪酸可能在微量"松散"铁存在情况下成为重要的有毒成分。Objective Free fatty acids from tobacco smoke may be important toxic elements since they can form a lipophilic complex with ferrous iron and then transport the iron into mammalian cells. Although such iron loading was earlier found to increase the oxidative susceptibility of cell membrane polyunsaturated fatty acids, additional toxic effects of fatty acid：iron complexes are little known. Methods Using simple eukaryotic cells of Saccharomyces cerevisiae, the synergistic effets of fatty acid：iron on yeast cytotoxicity and mutagenesis were investigated. The fatty acids-mediated iron depsition in the mitocchondria and lipid oxidation, and the subsequent reactive oxygen species generation were also studied. Results The combination of iron and free fatty acids was markedly toxic, although neither single constituent had a detectable effect on yeast viability and mutagenesis. This toxicity was prevented when yeast suspensions were incubated with nitrogen, suggesting that reactive oxygen generated by mitochondrial metabolism may be involved. Indeed, respiration defective（ρ 0） yeast were relatively protected against iron：fatty acid-induced toxicity. Yeasts endowed with enhanced iron storage capability through overexpression of CCC1 were similarly protected. The cytotoxic effects of iron ＋ fatty acids were most likely mediated by oxidant damage to membrane polyunsaturated fatty acids inasmuch as supplementation of yeast cultures with α-tocopherol or a ＇lazaroid＇ compound（inhibitors of peroxidation of polyunsaturated fatty acids） also protected against killing. Conclusion The toxic effects of iron overload caused by iron：fatty acid complexes may be implicated in the mitochondrial metabolism. Furthermore, if these observations in yeast are pertinent to the progressive pulmonary damage associated with cigarette smoking, they imply that the seemingly innocuous fatty acids existed in tobacco smoke mayrepresent important toxic elements in the presence of trace amounts of ‘loose＇ iron.

关 键 词：游离脂肪酸 铁 线粒体 氧化应激 酵母 

分 类 号：R589.2[医药卫生—内分泌]