Purohit Vishnudutt, Russo Denise, Salin Marvin
Biomedical Research Branch/Division of Basic Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 6000 Executive Boulevard, Suite 402, Bethesda, MD 20892-7003, USA.
Alcohol. 2003 Jun;30(2):93-7. doi: 10.1016/s0741-8329(03)00132-0.
The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on the "Role of Iron in Alcoholic Liver Disease" at Bethesda, Maryland, USA, October 2002. Alcoholic liver disease is a major cause of illness and death in the United States. Oxidative stress plays a key role in the pathogenesis of alcoholic liver disease. Iron can induce oxidative stress by catalyzing the conversion of superoxide and hydrogen peroxide to more potent oxidants such as hydroxyl radicals, which can cause tissue injury by initiating lipid peroxidation and causing oxidation of proteins and nucleic acids. Increasing evidence supports the suggestion that iron plays a significant role in the pathogenesis of alcoholic liver disease by exacerbating oxidative stress. Understanding the underlying mechanisms by which iron participates in the initiation and development of alcoholic liver disease may help design strategies for the treatment and prevention of the disease. For this symposium, nine speakers were invited to address the following issues: (1) iron intake from foods and dietary supplements; (2) hepatic iron overload in alcoholic liver disease; (3) iron-dependent activation of nuclear factor-kappa B (NF-kappaB) in Kupffer cells; (4) iron and cytochrome P450 2E1 (CYP2E1)-dependent oxidative stress and liver toxicity; (5) iron-induced oxidative stress in alcoholic hepatic fibrogenesis; (6) hemochromatosis and alcoholic liver disease; (7) iron as a co-morbid factor in nonhemochromatotic liver diseases; (8) iron and liver cancer; and (9) iron chelators and iron toxicity. On the basis of these presentations, it is concluded that heavy alcohol intake can result in increased accumulation of iron in the liver, in both hepatocytes and Kupffer cells. Iron-induced oxidative stress may promote the severity of alcoholic liver disease by (1) inducing NF-kappaB activation and subsequently increasing transcription of proinflammatory cytokines in Kupffer cells; (2) exacerbating CYP2E1-induced oxidative stress, especially in hepatocytes, through production of more toxic hydroxyl radicals; (3) stimulating hepatic stellate cells to produce excess amount of collagen and other matrix proteins that can lead to fibrosis; and (4) causing DNA damage and mutations that promote the development of liver cancer. Dietary iron supplements may further exacerbate the severity of alcoholic liver disease by increasing the magnitude of oxidative stress. We hope that the studies presented will stimulate further research in this exciting area.
美国国立酒精滥用与酒精中毒研究所及美国国立卫生研究院膳食补充剂办公室于2002年10月在美国马里兰州贝塞斯达主办了一场关于“铁在酒精性肝病中的作用”的研讨会。酒精性肝病是美国疾病和死亡的主要原因。氧化应激在酒精性肝病的发病机制中起关键作用。铁可通过催化超氧化物和过氧化氢转化为更强效的氧化剂（如羟基自由基）来诱导氧化应激，羟基自由基可通过引发脂质过氧化以及导致蛋白质和核酸氧化而引起组织损伤。越来越多的证据支持铁通过加剧氧化应激在酒精性肝病发病机制中起重要作用这一观点。了解铁参与酒精性肝病发生和发展的潜在机制可能有助于设计该疾病的治疗和预防策略。在本次研讨会上，邀请了9位演讲者探讨以下问题：（1）食物和膳食补充剂中的铁摄入；（2）酒精性肝病中的肝脏铁过载；（3）库普弗细胞中铁依赖性核因子κB（NF-κB）的激活；（4）铁与细胞色素P450 2E1（CYP2E1）依赖性氧化应激及肝脏毒性；（5）铁诱导的氧化应激在酒精性肝纤维化中的作用；（6）血色素沉着症与酒精性肝病；（7）铁作为非血色素沉着性肝病的共病因素；（8）铁与肝癌；（9）铁螯合剂与铁毒性。基于这些报告得出结论，大量饮酒可导致肝脏（包括肝细胞和库普弗细胞）中铁的积累增加。铁诱导的氧化应激可能通过以下方式促进酒精性肝病的严重程度：（1）诱导NF-κB激活，随后增加库普弗细胞中促炎细胞因子的转录；（2）通过产生更多有毒的羟基自由基加剧CYP2E1诱导的氧化应激，尤其是在肝细胞中；（3）刺激肝星状细胞产生过量的胶原蛋白和其他基质蛋白，从而导致纤维化；（4）引起DNA损伤和突变，促进肝癌的发展。膳食铁补充剂可能通过增加氧化应激程度进一步加剧酒精性肝病的严重程度。我们希望所展示的研究将激发该令人兴奋领域的进一步研究。
