Cederbaum Arthur I
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, Box 1603, New York, NY 10029, USA.
Alcohol. 2003 Jun;30(2):115-20. doi: 10.1016/s0741-8329(03)00104-6.
Iron plays a critical role in catalyzing the formation of potent oxidants. Increases in iron content enhance oxidative stress, whereas removal of iron deceases such stress. An association between iron and alcoholic liver injury has been proposed. The ability of iron to modulate the biochemical and toxicologic actions of cytochrome P450 2E1 (CYP2E1) has been evaluated by using isolated microsomes and intact liver cells. The ability of different iron complexes to stimulate microsomal lipid peroxidation and hydroxyl radical production during reduced form of nicotinamide adenine dinucleotide phosphate (NADPH)- and reduced form of nicotinamide adenine dinucleotide (NADH)-dependent electron transfer has been characterized. Certain iron complexes have been shown to be effective in promoting lipid peroxidation; others are better catalysts of hydroxyl radical production as a complex pattern has been found. Reactive oxygen production, lipid peroxidation, and interaction with iron chelates have been shown to be enhanced with microsomes isolated from ethanol-treated rats with elevated levels of CYP2E1. This increase was prevented by anti-CYP2E1 immunoglobulin (Ig)G or chemical inhibitors of CYP2E1. Thus, in the presence of iron complexes, microsomes enriched in CYP2E1 are especially reactive in generation of reactive oxygen species. To assess the toxicologic significance of this iron-CYP2E1 interaction, iron (ferric-nitrilotriacetate) was added to HepG2 cells, which were engineered to express the human CYP2E1. Ferric-nitrilotriacetate produced a greater toxicity in the CYP2E1-expressing HepG2 cells than that in control HepG2 cells. This enhanced, synergistic toxicity was blocked by antioxidants and inhibitors of CYP2E1. Mitochondrial membrane potential and ATP levels were decreased, and damage to the mitochondria played a critical role in the CYP2E1-plus-iron-dependent toxicity. These results support the suggestion that low concentrations of iron and polyunsaturated fatty acids can act as priming or sensitizing factors for CYP2E1-induced injury in HepG2 cells and hepatocytes. Such interactions may play a role in alcohol-induced liver injury.
铁在催化强氧化剂的形成过程中起着关键作用。铁含量的增加会增强氧化应激，而去除铁则会降低这种应激。铁与酒精性肝损伤之间的关联已被提出。通过使用分离的微粒体和完整的肝细胞，评估了铁调节细胞色素P450 2E1（CYP2E1）生化和毒理学作用的能力。已对不同铁络合物在还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和还原型烟酰胺腺嘌呤二核苷酸（NADH）依赖性电子转移过程中刺激微粒体脂质过氧化和羟基自由基产生的能力进行了表征。某些铁络合物已被证明在促进脂质过氧化方面有效；由于发现了复杂的模式，其他铁络合物则是更好的羟基自由基产生催化剂。从乙醇处理且CYP2E1水平升高的大鼠中分离出的微粒体，其活性氧生成、脂质过氧化以及与铁螯合物的相互作用均增强。抗CYP2E1免疫球蛋白（Ig）G或CYP2E1的化学抑制剂可阻止这种增加。因此，在存在铁络合物的情况下，富含CYP2E1的微粒体在产生活性氧方面特别活跃。为了评估这种铁 - CYP2E1相互作用的毒理学意义，将铁（三乙酸铁腈）添加到经过基因工程改造以表达人CYP2E1的HepG2细胞中。三乙酸铁腈在表达CYP2E1的HepG2细胞中产生的毒性比在对照HepG2细胞中更大。这种增强的协同毒性被抗氧化剂和CYP2E1抑制剂所阻断。线粒体膜电位和ATP水平降低，线粒体损伤在CYP2E1加铁依赖性毒性中起关键作用。这些结果支持以下观点：低浓度的铁和多不饱和脂肪酸可作为HepG2细胞和肝细胞中CYP2E1诱导损伤的引发或致敏因素。这种相互作用可能在酒精性肝损伤中起作用。
