The role of metals in ischemia/reperfusion injury of the liver.
ABSTRACT 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.
- SourceAvailable from: Irwin Cheah[Show abstract] [Hide abstract]
ABSTRACT: Since its discovery, the unique properties of the naturally occurring amino acid, L-ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine), have intrigued researchers for more than a century. This widely distributed thione is only known to be synthesized by non-yeast fungi, mycobacteria and cyanobacteria but accumulates in higher organisms at up to millimolar levels via an organic cation transporter (OCTN1). The physiological role of EGT has yet to be established. Numerous in vitro assays have demonstrated the antioxidant and cytoprotective capabilities of EGT against a wide range of cellular stressors, but an antioxidant role has yet to be fully verified in vivo. Nevertheless the accumulation, tissue distribution and scavenging properties, all highlight the potential for EGT to function as a physiological antioxidant. This article reviews our current state of knowledge. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.Biochimica et Biophysica Acta 10/2011; 1822(5):784-93. · 4.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Liver resections are frequently associated with significant ischemia-reperfusion (I-R) injury of the liver remnant. The aim of this study was to investigate whether deferoxamine (DFO) can ameliorate I-R injury during major hepatectomies performed under vascular exclusion of the liver in a porcine model. Twelve female domestic pigs were divided into control (n = 6) and DFO treatment (n = 6) groups and subjected to 150 min. liver ischemia followed by 70% hepatectomy and 24 hours reperfusion. Pigs in the DFO group received a continuous intravenous infusion of 100 mg/kg DFO. Liver remnant injury was evaluated by liver function tests, hepatic histology as well as serum and liver tissue malondialdehyde (MDA) concentrations. Deferoxamine-treated animals had reduced total bilirubin, gamma-glutamyl transferase and ammonia levels as well as hepatocyte necrosis and oxidative injury. In a subsequent randomized clinical trial using DFO for I-R protection during major liver surgery, preliminary results revealed amelioration of hepatocellular damage, oxidative and inflammatory serum markers and apoptotic response in liver remnant biopsies.Hemoglobin 06/2010; 34(3):265-77. · 0.96 Impact Factor
- [Show abstract] [Hide abstract]
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.Toxicology 11/2011; 291(1-3):93-101. · 3.75 Impact Factor