Stål P, Johansson I, Ingelman-Sundberg M, Hagen K, Hultcrantz R
Department of Gastroenterology and Hepatology, Karolinska Institutet, Haddinge University Hospital, Sweden.
J Hepatol. 1996 Oct;25(4):538-46. doi: 10.1016/s0168-8278(96)80214-5.
BACKGROUND/AIMS: Clinical experience and studies with experimental animal models indicate a synergistic hepatotoxic effect of dietary iron overload and chronic alcohol ingestion. In order to elucidate the mechanism underlying this synergism, we examined the hepatic levels of ethanol-inducible cytochrome P450 2E1, glutathione and malondialdehyde, and the effect of iron chelation with desferrioxamine, in livers from rats treated with iron and/or ethanol.
Animals received diets with or without 2.5-3% carbonyl iron for 6-9 weeks, followed by an ethanol-containing diet or a liquid control diet for 5-9 weeks. Desferrioxamine was administered subcutaneously with mini-osmotic pumps. Alanine aminotransferase activity in serum and hepatic contents of glutathione and malondialdehyde were determined. The hepatic level of cytochrome P450 2E1 was determined with Western Blotting using a specific polyclonal antibody.
The combination of iron and alcohol led to a marked increase in serum alanine aminotransferase activity as compared with all other treatment groups, and iron chelation with desferrioxamine reversed these increases. Treatment with alcohol alone led to slightly increased aminotransferases compared with controls. The level of cytochrome P450 2E1 was significantly elevated in microsomes isolated from ethanol-treated rats, but neither additional iron supplementation nor desferrioxamine influenced this level significantly. Glutathione contents were increased in the livers of animals treated with iron and/or ethanol. Malondialdehyde values were increased in iron-treated animals, whereas neither ethanol nor desferrioxamine altered malondialdehyde levels significantly.
The toxic effects exerted by the combination of iron overload and chronic ethanol feeding on rat liver are dependent on a pool of chelatable iron. The hepatic level of cytochrome P450 2E1 is markedly induced by ethanol but not further altered by iron overload. Neither increased lipid peroxidation nor depletion of hepatic glutathione levels can explain the synergistic hepatotoxic effects of iron and ethanol in this model.
背景/目的：临床经验及对实验动物模型的研究表明，饮食中铁过载与长期摄入酒精具有协同肝毒性作用。为阐明这种协同作用的潜在机制，我们检测了铁和/或乙醇处理的大鼠肝脏中乙醇诱导的细胞色素P450 2E1、谷胱甘肽和丙二醛的水平，以及去铁胺铁螯合的效果。
动物接受含或不含2.5 - 3%羰基铁的饮食6 - 9周，随后接受含乙醇饮食或液体对照饮食5 - 9周。用微型渗透泵皮下注射去铁胺。测定血清丙氨酸氨基转移酶活性以及肝脏中谷胱甘肽和丙二醛的含量。使用特异性多克隆抗体通过蛋白质印迹法测定细胞色素P450 2E1的肝脏水平。
与所有其他治疗组相比，铁与酒精联合导致血清丙氨酸氨基转移酶活性显著升高，而去铁胺铁螯合可逆转这些升高。单独用酒精处理与对照组相比导致氨基转移酶略有升高。从乙醇处理的大鼠分离的微粒体中细胞色素P450 2E1水平显著升高，但额外补充铁或去铁胺均未显著影响该水平。铁和/或乙醇处理的动物肝脏中谷胱甘肽含量增加。铁处理的动物丙二醛值升高，而乙醇和去铁胺均未显著改变丙二醛水平。
铁过载与长期喂食乙醇联合对大鼠肝脏产生的毒性作用取决于可螯合铁池。细胞色素P450 2E1的肝脏水平由乙醇显著诱导，但不受铁过载进一步影响。脂质过氧化增加和肝脏谷胱甘肽水平耗竭均不能解释该模型中铁和乙醇的协同肝毒性作用。
