Abstract
To delineate the active free radical species mediating the toxic effects of autoxidizing dihydroxyfumarate (DHF), isolated rabbit right ventricular papillary muscles were exposed to 4.5 mM DHF in the presence of FeCl3, ADP and bovine albumin. In the absence of free radical scavengers a 47.3 ± 11.5 % (mean ± standard deviation) depression in contractile force was noted over 60 minutes. Neither the combination of superoxide dismutase (SOD) 3 200 u/cc and catalase (CAT) 2 950 u/cc nor mannitol 0.1 M provided statistically significant protection. Deferoxamine mesylate (DFX) 10 mg/cc (15 mM) did provide significant protection of muscle function both in the presence and absence of SOD and CAT (p < 0.01). The degree of protection conferred by DFX alone was statistically similar to that of DFX with SOD and CAT. This data suggests the involvement of an iron-oxygen complex not dependent on superoxide or hydrogen peroxide for its formation and not readily scavenged by mannitol. The perferryl ion may be representative of such a species. Alternatively, a reactive complex similiar to the ‘Crypto-OH’ radical proposed by Youngman may be formed by the reaction of DHF with iron and oxygen.
Similar content being viewed by others
References
Halliwell B, Gutteridge JMC: The importance of free radicals and catalytic metals ions in human disease. Molec Aspects Med 8:89–193, 1985
Cohen G: The generation of hydroxyl radicals in biological systems: toxicological aspects. Photochem Photobiol 28:669–675, 1978
Slater TF: Free radical mechanisms in tissue injury. Biochem J 222:1–15, 1984
Halliwell B, Gutteridge JMC: Oxygen toxicity, oxygen radicals, transition metals and disease: Biochem J 219:1–14, 1984
Proctor PH, Reynolds ES: Free radicals and disease in man. Physiol Chem Phys Med NMR 16:175–195, 1984
Clark IA, Cowden WB, Hunt NH: Free radical-induced pathology. Med Res Rev 5:297–332, 1985
Youngman RJ: Oxygen activation: Is the hydroxyl radical always biologically relevant? Trends Biochem Sci 9:280–284, 1984
Aust SD, Morehouse LA, Thomas CE: Role of metals in oxygen radical reactions. J Free Rad Biol Med 1:3–25, 1985
Halliwell B: Superoxide dependent formation of hydroxyl radicals in the presence of iron salts. FEBS Lett 96:238–242, 1978
Winterbourn CC: Lactoferrin-catayyzed hydroxyl radical production. Biochem J 210:15–19, 1983
Rowley DA, Halliwell B: Superoxide-dependent formation of hydroxyl radicals from NADH and NADPH in the presence of iron salts. FEBS Lett 142:39–41, 1982
Czapski G: On the use of OH scavengers in biological systems. Isr J Chem 24:29–32, 1984
Flitter W, Rowley DA, Halliwell B: Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. What is the physiologic iron chelator? FEBS Lett 158:310–312, 1983
Graf E, Mahoney JR, Bryant RG, Eaton JW. Iron catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site. J Biol Chem 259:3620–3624, 1984
Rowley DA, Halliwell B: Formation of hydroxyl radicals from hydrogen peroxide and iron salts by superoxide and ascorbate-dependent mechanisms: Relevance to the pathology of rheumatoid disease. Clin Sci 64:649–653, 1983
Halliwell B: Superoxide and superoxide dependent formation of hydroxyl radicals are important in oxygen toxicity. Trends Biochem Sci 7:270–272, 1982
Czapski G, Ilan YA: On the generation of the hydroxylation agent from superoxide radical. Can the Haber-Weiss reaction be the source of OH radicals? Photochem Photobiol 28:651–653, 1978
Halliwell B: Generation of hydrogen peroxide, superoxide and hydroxyl radicals during the oxidation of dihydroxyfumaric acid by peroxidase. Biochem J 1963:441–448, 1977
Autor AP, McLennan G, Fox AW: Oxygen free radicals generated by dihydroxyfumarate and ionizing radiation: Cytotoxic effects on isolated pulmonary macrophages. In: Bbatnager RS (ed) The Molecular Basis of Environmental Toxicity. Ann Arbor Science Publishing, Ann Arbor, 1980, pp 51–66
Halliwell B, DeRycher J: Superoxide and peroxidase catalyzed reactions. Oxidation of dihydroxyfumarate, NADH, and dithiothreitol by horseradish peroxidase. Photochem Photobiol 28:757–763, 1978
Halliwell B: Generation of hydrogen peroxide, superoxide and hydroxyl radicals during the oxidation of dihydroxyfumaric acid by peroxidase. Biochem J 1963:441–448, 1977
Youngman RJ, Elstner EF: Oxygen species in paraquat toxicity: The Crypto-OH radical. FEBS Lett 129:265–268, 1981
Weglicki WB, Mak IT, Misra HP, Dickens BF: Free radical and phospholipase-induced degradation of structured phospholipids of lysosomes during free radical injury (Abstr). Fed Proc 43:701, 1984
Goldberg B, Stern A: The role of superoxide anion as a toxic species in the erythrocyte. Arch Biochem Biophys 178:218–225, 1977
Fischer LJ, Hamburger SA: Dimethylurea: A radical scavenger that protects isolated pancreatic islets from the effects of alloxan and dihydroxyfumarate exposure. Life Sci 26:1405–1409, 1980
Fridovich I: Superoxide radical: An endogenous toxicant. Ann Rev Pharmacol Toxicol 23:239–257, 1983
Baldwin Deardorff M: Leukocyte generated reduced oxygen intermediate effects on rabbit papillary muscle mechanics. Doctoral Disseration, Medical College of Virginia, 1986, p 87
Barber DJW, Thomas JK: Reactions of radicals with lecithin bilayers. Radiat Res 74:51–65, 1978
Goldstein S, Czapski G: Mannitol as an OH scavenger in aqueous solutions in biological systems. Int J Radiat Biol 46:725–729, 1984
Gutteridge JMC, Richmond R, Halliwell B: Inhibition of the iron-catalyzed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem J 184:469–472, 1979
Tien M, Svingen BA, Aust SD: Superoxide dependent lipid peroxidation. Fed Proc 40:179–182, 1981
Bucher JR, Tien M, Aust SD: The requirement for ferric in the initiation of lipid peroxidation by chelated ferrous iron. Biochem Biophys Res Comm 111:777–784, 1983
Morehouse LA, Tien M, Bucher JR, Aust SD: Effects of hydrogen peroxide on the initiation of microsomal lipid peroxidation. Biochem Pharmacol 32:123–127, 1983
Mirrotti G, Aust SD: The requirement of iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide. J Biol Chem 262:1098–1104, 1987
Koppenol WH, Liebman JF: The oxidizing nature of the hydroxyl radical. A comparison with the ferryl ion (FeO2+). J Phys Chem 88:99–101, 1984
Gutteridge JMC: The role of superoxide and hydroxyl radicals in phospholipid peroxidation catalyzed by iron salts. FEBS Lett 150:454–458, 1982
Rechnagel RO, Glende EA: Lipid peroxidation: A specific form of cellular injury. In: Lee DHF, Falls HL, Murphy SD, Geigh SR (eds) Handbook of Physiology: Reactions to Environmental Agents. American Physiologic Society, Williams and Wilkins Co, Baltimore, MD, 1977, pp 591–601
Shimizu N, Kobayashi K, Hayaski K: The reaction of superoxide radical with catalase. Mechanism of the inhibition of catalase by superoxide radical. J Biol Chem 259:4414–4418, 1984
Bray RC, Cockle SA, Fielden EM, Roberts PB, Rotilio G, Calabrese L: Reduction and inactivation of superoxide dismutase by hydrogen peroxide. Biochem J 139:43–48, 1974
Kono Y, Fridovich I: Superoxide radical inhibits catalase. J Biol Chem 257:5751–5754, 1982
Hallwell B: Use of desferrioxamine as a ‘probe’ for iron-dependent formation of hydroxyl radicals. Evidence for a direct reaction between Desferol and the superoxide radical. Biochem Pharmacol 34:229–233, 1985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wood, M.A., Hess, M.L. The effects of dihydroxyfumarate on isolated rabbit papillary muscle function: evidence for an iron dependent non-hydroxyl radical mechanism. Mol Cell Biochem 78, 161–167 (1987). https://doi.org/10.1007/BF00229690
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00229690