The Role of Metals in Ischemia/Reperfusion Injury of the Liver

Mayo Clinic - Rochester, Рочестер, Minnesota, United States
Seminars in Liver Disease (Impact Factor: 4.95). 03/1996; 16(1):31-8. DOI: 10.1055/s-2007-1007216
Source: PubMed


Based on current information, we have described the role that metals play in potentiating and ameliorating liver I/R injury. To date, most of the data have focused on the deleterious effects of free iron in mediating I/R injury. Several therapeutic strategies have proven useful in animal models to counteract the effect of iron as a potentiator of I/R injury. These approaches have predominantly centered on the role of iron chelation using DFO and DFO conjugates. The data suggest that chelation of iron may prove useful in preventing I/R injury such as occurs in liver transplantation. Indeed, enough data are now available to initiate and support clinical trials (e.g., addition of DFO conjugates to explant storage solutions). The role of copper, however, is less well defined. Copper is important for the function of copper-zinc SOD. However, free copper may be as injurious as free iron. Further studies are needed to clarify the role of copper in I/R-induced hepatocellular necrosis. Selenium has a well-defined antioxidant role as part of GSH peroxidase (GSH antioxidant pathway). More recent data suggest that selenium may also act as an antioxidant through selenoprotein P, but the role of selenoprotein P in I/R injury remains to be defined. Finally, zinc appears to function as an antioxidant in less well-defined pathways. Further studies are needed to identify the fundamental mechanisms by which zinc may ameliorate oxidative damage during I/R injury. These data demonstrate that metals play a critical role in I/R injury of the liver and remain a fruitful area for investigation and development of therapeutic strategies.

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    • "In addition, it has been shown that DFO prevents ROS formation by inhibiting the catalytic role of iron in the Fenton reaction (Arora and Gores, 1996). In vitro studies have shown that DFO blocks ROS production (Guelman, 2004). "
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    ABSTRACT: Deferoxamine (DFO) is a recognized iron chelator which has been shown to exert nephroprotection in models of toxic nephropathies. In the present work the potential protective effects of DFO against Cr(VI)-induced nephrotoxicity and oxidant stress were evaluated. Rats were injected with a single injection (15mg/kg, s.c.) of potassium dichromate (K(2)Cr(2)O(7)). DFO was given as a single i.p. injection 30min before K(2)Cr(2)O(7) administration at three different doses (100, 200 and 400mg/kg). It was found that DFO pretreatment attenuated, in a dose-dependent way, K(2)Cr(2)O(7)-induced renal dysfunction and structural alterations evaluated by serum creatinine, blood urea nitrogen, creatinine clearance, proteinuria, plasma glutathione peroxidase activity, urinary excretion of N-acetyl-β-d-glucosaminidase and histological analyses. Furthermore, DFO prevented the K(2)Cr(2)O(7)-induced renal oxidant stress and the decrease in the activity of the antioxidant enzymes superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and catalase. Finally it was found that DFO, at 400mg/kg, decreases renal Cr(VI) content which prompted us to evaluate the potential Cr(VI) chelating properties of this compound. Indeed was found in an in vitro assay that DFO was an effective Cr(VI) chelator with an IC(50) of 800μg. In additional groups of rats was found that DFO posttreatment was ineffective to attenuate K(2)Cr(2)O(7)-induced nephrotoxicity and renal oxidant stress. Furthermore, DFO was unable to modify urinary excretion of total chromium. The nephroprotective effect of DFO against Cr(VI)-induced nephrotoxicity and oxidant stress may be explained, at least partially, by the ability of DFO to chelate Cr(VI) and to attenuate renal Cr(VI) content. However, it cannot be excluded that the ability of DFO to chelate iron may also be involved in the protection observed in our study.
    Full-text · Article · Nov 2011 · Toxicology
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    • "It has been observed that when administered during reperfusion most of these compounds exerted considerable protection against IR-induced injury. Desferrioxamine , a strong and rather specific iron chelator that is often used in clinical settings, has been extensively studied in such models and repeatedly found to be protective against IRinduced injury168169170171. However, it should be noted that desferrioxamine, due to its hydrophilicity and its relatively high molecular weight (about 500 Da) is not able to penetrate through plasma membranes by passive diffusion. "
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    ABSTRACT: Ischemia-reperfusion (IR) injury is a multifactorial process triggered when the liver or other organs are transiently subjected to reduced blood supply followed by reperfusion. It has been shown that "reactive oxygen species" (ROS) are generated during ischemia and reperfusion and may represent pivotal mediators of the ensuing pathological complications. In some cases, however, moderate production of ROS may exert protective effects, a phenomenon presumably related to "ischemic preconditioning". This review will focus mainly on: a) describing the sources and the biochemical mechanisms of ROS generation during ischemia and reperfusion, b) discussing current developments in understanding the biochemical pathways by which ROS may induce toxic or protective effects, c) critically evaluating the results of previous attempts to counteract the toxic effects of ROS by using a variety of antioxidant and transition metal-chelating agents, and d) if feasible, proposing potential new pharmaceutical agents aimed at ameliorating ROS-inducing deleterious effects during reperfusion. It is concluded that ROS are generated from different sources, at different periods during IR, and may act by a variety of not well understood biochemical mechanisms which ultimately lead to cell damage and tissue failure.
    Full-text · Article · Feb 2006 · Current Pharmaceutical Design
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    • "Iron-dependent processes play a pivotal role in the development of oxidative-induced cell injury. Specifically, the generation of hydroxyl radicals from hydroperoxide and the formation of aldehydes and lipid peroxy radicals from lipid hydroperoxides are catalyzed by redox-active metals, including iron and copper [17,20,21]. MPO and NO are known sources of free radicals and induce reduction of ferritin-Fe3+ into free Fe2+ contributing to oxidative damage [22,23]. "
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    ABSTRACT: The exogenous administration of Insulin-like Growth Factor-I (IGF-I) induces hepatoprotective and antifibrogenic actions in experimental liver cirrhosis. To better understand the possible pathways behind the beneficial effect of IGF-I, the aim of this work was to investigate severe parameters involved in oxidative damage in hepatic tissue from cirrhotic animals treated with IGF-I (2 microg x 100 g(-1) x day(-1)). Iron and copper play an important role in oxidative mechanisms, producing the deleterious hydroxyl radical (*OH) that peroxides lipid membranes and damages DNA. Myeloperoxidase (MPO) and nitric oxide (NO) are known sources of free radicals and induce reduction of ferritin-Fe3+ into free Fe2+, contributing to oxidative damage. Liver cirrhosis was induced by CCl4 inhalation in Wistar male rats for 30 weeks. Healthy controls were studied in parallel (n = 10). Fe and Cu were assessed by atomic absoption spectrometry and iron content was also evaluated by Perls' staining. MPO was measured by ELISA and transferrin and ferritin by immunoturbidimetry. iNOS expression was studied by immuno-histochemistry. Liver cirrhosis was histologically proven and ascites was observed in all cirrhotic rats. Compared to controls untreated cirrhotic rats showed increased hepatic levels of iron, ferritin, transferrin (p < 0.01), copper, MPO and iNOS expression (p < 0.01). However, IGF-treatment induced a significant reduction of all these parameters (p < 0.05). the hepatoprotective and antifibrogenic effects of IGF-I in cirrhosis are associated with a diminution of the hepatic contents of several factors all of them involved in oxidative damage.
    Full-text · Article · Feb 2005 · BMC Gastroenterology
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