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UNC-Chapel Hill ENVR 442 - Iron chelators can protect against oxidative stress through ferryl heme reduction

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Iron chelators can protect against oxidative stress through ferryl heme reductionMaterial and methodsMaterialsChelatorsHorse myoglobinMeasurement of rate constant for ferryl decayMeasurement of heme-to-protein cross-linkingResultsDiscussionAcknowledgmentReferencesOriginal ContributionIron chelators can protect against oxidative stress throughferryl heme reductionBrandon J. Reedera,⁎, Robert C. Hiderb, Michael T. WilsonaaDepartment of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UKbDepartment of Pharmacy, King’s College London, Franklin–Wilkins Building, 150 Stamford Street, London SE1 9NN, UKReceived 14 June 2007; revised 3 August 2007; accepted 6 August 2007Available online 21 August 2007AbstractIron chelators such as desferrioxamine have been shown to ameliorate oxidative damage in vivo. The mechanism of this therapeutic actionunder non-iron-overload conditions is, however, complex, as desferrioxamine has properties that can impact on oxidative damage independent ofits capacity to act as an iron chelator. Desferrioxamine can act as a reducing agent to remove cytotoxic ferryl myoglobin and hemoglobin and hasrecently been shown to prevent the formation of a highly cytotoxic heme-to-protein cross-linked derivative of myoglobin. In this study we haveexamined the effects of a wide range of iron chelators, including the clinically used hydroxypyridinone CP20 (deferriprone), on the stability offerryl myoglobin and on the formation of heme-to-protein cross-linking. We show that all hydroxypyridinones, as well as many other ironchelators, are efficient reducing agents of ferryl myoglobin. These compounds are also effective at preventing the formation of cytotoxicderivatives of myoglobin such as heme-to-protein cross-linking. These results show that the use of iron chelators in vivo may ameliorate oxidativedamage under conditions of non-iron overload by at least two mechanisms. The antioxidant effects of chelators in vivo cannot, therefore, beattributed solely to iron chelation.© 2007 Elsevier Inc. All rights reserved.Keywords: Myoglobin; Ferryl; Iron chelators; Oxidative damage; Heme-to-protein cross-linking; Free radicalsThe iron chelator desferrioxamin e (DFO) has been used forseveral decades to prevent iron overl oad in patients (e.g., fromregular blood transfusions required to treat thalassem ia). Due toits ability to inhibit the redox activity of transition metalsthrough chelation, DFO has also been used to examine themechanisms of oxidative stress caused by iron in many diseasestates. Positive therapeutic effects are often credited to theability of DFO to prevent Fenton chemistry induced by “free”iron (i.e., not bound to catalytic proteins or transferrin/ferritin),and hence inference is made regarding the importance of freeiron in the pathogenesis of certain disease conditions. Somehave challenged this as the sole interpretation, however, iden-tifying in vivo properties of DFO that can impact on oxidativereactions independent of its ability as an iron chelator. One ofthese effects is the capacity of DFO to act as a reducing agent,preventing oxidation of, for example, membrane lipids byremoving high oxidation states of heme iron, such as ferrylmyoglobin (Mb) or hemoglobin (Hb) [1–4]. In addition to beingan electron donor DFO has been cited to possess several otherproperties, including acting in vivo as a substrate forperoxidases [5] and a scavenger of radicals [5–7].With such a large repertoire of actions that can affect oxi-dative reactions, the interpretation of the results of many studiesshowing that DFO ameliorates oxidative damage is ambiguouswith respect to the initiator of the cellular damage. This isespecially significant in diseases in which respiratory hemeproteins may be involved. Under these circumstances both intactand degraded forms of the heme protein, from which iron may beliberated, could potentially play a role in the mechanism ofoxidative damag e. One such condition is acute renal failure afterrhabdomyolysis (muscle trauma). The presence of Mb in theAvailable online at www.sciencedirect.comFree Radical Biology & Medicine 44 (2008) 264 – 273www.elsevier.com/locate/freeradbiomedAbbreviations: CP02, 1-ethyl-3-hydroxypyrid-2-one; CP20, 1,2-dimethyl-3-hydroxypyrid-4-o ne; CP358, 1,6 -dimethyl-2 -( N-4′,N-propylsuccinamido )methyl-3-hydroxypyridin-4-one; DFO, desferrioxamine; Hb, hemoglobin; Mb,myoglobin; Mb–X, heme-to-protein cross-linked myoglobin.⁎Corresponding author. Fax: +44 1206 872592.E-mail address: [email protected] (B.J. Reeder).0891-5849/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.freeradbiomed.2007.08.006kidney after rhabdomyolysis results in oxidative tissue damage,causing renal dysfunction [8] . Another is subarachnoid brainhemorrhaging in which Hb is released into the cerebrospinalfluid, often leading to delayed vasospasm resulting from theformation of potent vasoactive lipid oxidation products [9].Itisgenerally believed that free iron plays an important role in thepathogenesis of these conditions. The evidence to support thishypothesis almost exclusively comes from in vivo studies usingiron chelator compounds such as DFO [10–12]. An alternativeview is that heme proteins such as Mb and Hb generate thesepotent vasoactive lipid oxidation products through an enzy-matic-like process in which DFO interferes [13].Evidence to support the role of heme proteins as a majorcomponent in the mechanism of oxid ative damage afterhemolytic injuries comes from studies of heme oxygenaseknockout and knock-in animal models. Heme oxyganease-1 isan enzym e that degrades heme, liberating iron. It thus preventsheme-induced oxidative reactions while potentially exacerbat-ing free-iron-induced oxidative reactions. In models of rhabdo-myolysis heme oxygenase-1 knockout animals exhibit moredeleterious effects than control animals [14]. The knockoutanimals exhibit elevated levels of plasma creatine and lactatedehydrogenase, showing a higher mortality rate compared withcontrol animals. In addition the overexpression of hemeoxygenase-1 in an animal model of subarachnoid hemorrhagehas been found to have a positive therapeutic effect [15]. Thesetwo studies indicate that intact heme, rather than free iron, isimportant in the mechanism of oxidative damage, showing theheme oxygenase-1 to be indispensable in protecting againstheme protein-induced toxicity in vivo. Furthermore, it may benoted


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