PROTECTIVE EFFECT OF MELATONIN AGAINST IRON OVERLOAD-INDUCED TOXICITY IN RATS
Keywords:
Iron overload, Metallothionein, Melatonin, AntioxidantsAbstract
Objective: Iron overload is a serious, potentially fatal disorder characterized by the deposition of excess iron within tissues leading to functional impairment and reduced life expectancy. The present study was designed to evaluate the efficacy of melatonin in protecting rats against iron overload-induced toxicity.
Methods: Twenty-four adult male rats were randomly divided into four groups: the control, iron overload group, melatonin group and iron overload+melatonin group. Rats received ferric hydroxide poly maltose at a dose of 50 mg/kg body weight (three doses per week) for four weeks through intra peritoneal injections and received the melatonin subcutaneously (10 mg/kg/day) for four weeks.
Results: In iron overloaded rats, the iron status markers: serum, hepatic and renal tissues iron, Total Iron Binding Capacity (TIBC), transferrin and transferrin saturation percentage (TS %) were significantly increased, while a marked decrease in Unsaturated Iron Binding Capacity (UIBC) was demonstrated. The oxidative stress marker malondialdehyde (MDA) was significantly increased while a marked decrease in the catalase (CAT) and glutathione peroxidase (GPx) activities as well as in reduced glutathione (GSH) content accompanied with increased levels of metallothionein (MT) in hepatic and renal tissues were demonstrated. In addition, the liver and kidney functions were disturbed. Co-treatment with melatonin, significantly improved iron overload-induced alterations as indicated by the attenuation of the iron status disturbances, the reduction of the indices of liver and kidney functions and lipid peroxidation product and elevation of antioxidants and MT.
Conclusion: The study showed the potential effect of melatonin against iron overload–induced toxicity through its chelating effect on iron, elevation of MT and improvement of antioxidant status.
Â
Downloads
References
Conrad ME. Excess iron and catastrophic illness. Am J Hematol 1993;43:234-6.
Reddy AC, Lokesh BR. Effect of curcumin and eugenol on iron-induced hepatic toxicity in rats. Toxicology 1996;107:39-45.
Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics. 11th edition. New York: McGraw-Hill; 2006.
Shah SV, Alam MG. Role of iron in atherosclerosis. Am J Kidney Dis 2003;41(3 Suppl 1):S80-3.
Porter JB. A risk-benefit assessment of iron-chelation therapy. Drug Saf 1997;17:407-21.
Fraga CG, Oteiza PI. Iron toxicity and antioxidant nutrients. Toxicology 2002;180:23-32.
Reiter RJ. Melatonin: Clinical relevance. Best Pract Res Clin Endocrinol Metab 2003;17:273-85.
Zaminy A, Kashani IR, Barbarestani M, Hedayatpour A, Mahmoudi R, Vardasbi S, et al. Effects of melatonin on the proliferation and differentiation of rat adipose-derived stem cells. Indian J Plastic Surgery 2008;41:8-14.
Shirazi A, Haddadi GH, Ghazi-Khansari M, Abolhassani F, Mahdavi SR, Eshraghyan MR. Evaluation of melatonin for prevention of radiation myelopathy in irradiated cervical spinal cord. Yakhteh 2009;11:43-8.
L´opez-Burillo S, Tan DX, Mayo JC, Sainz RM, Manchester LC, Reiter RJ. Melatonin, xanthurenic acid, resveratrol, EGCG, Vitamin C and alpha lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions. J Pineal Res 2003;34:269-77.
Cuzzocrea S, Reiter RJ. Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol 2001;426:1-10.
Srinivasan V. Melatonin oxidative stress and neurodegenerative diseases. Indian J Exp Biol 2002;40:668-79.
Suresh C, Dennis AO, Heinz J, Vemuri MC, Chetty CS. Melatonin protection against lead-induced changes in human neuroblastoma cell cultures. Int J Toxicol 2006;25:459-64.
Zhao Y, Li H, Gao Z, Xu H. Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. Eur J Pharmacol 2005;509:195-200.
Shagirtha K, Muthumani M, Prabu SM. Melatonin abrogates cadmium induced oxidative stress related neurotoxicity in rats. Eur Rev Med Pharmacol Sci 2011;15:1039-50.
Stookey LL. Ferrozine-a new spectrophotometric reagent for iron. Anal Chem 1970;42:779-81.
Carter P. Spectrophotometric determination of serum iron at the submicrogram level with a new reagent (ferrozine). Anal Biochem 1971;40:450-8.
Cook JD. The measurement of serum transferrin receptor. Am J Med Sci 1999;318:269-76.
Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 1957;28:56-63.
Walters M, Gerade H. Ultramicromethod for the determination of conjugated and total bilirubin in serum or plasma. Microchem J 1970;15:231-43.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:269-75.
Doumas BT, Watson WA, Biggs HG. Albumin standards and the measurement of serum albumin with bromocresol green. Clin Chem Acta 1977;31:87-96.
Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470-5.
Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982;28:2077-80.
Foster LB, Hochholzer JM. A single-reagent manual method for directly determining urea nitrogen in serum. Clin Chem 1971;17:921-5.
Schirmeister J, Willmann H, Kiefer H. Critical evaluation of plasma creatinine as a test of glomerulus filtrate. Verh Dtsch Ges Inn Med 1964;70:678-81.
Ohkawa H, Ohishi W, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8.
Aebi H. Catalase in vitro. Methods Enzymol 1984;105:121-6.
Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967;70:158-69.
Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882-8.
Dabbagh AJ, Mannion T, Lynch SM, Frei B. The effect of iron overload on rat plasma and liver oxidant status in vivo. Biochem J 1994;300:799-803.
Onosaka S, Cherian MG. Comparison of metallothionein determination by polarographic and cadmium saturation methods. Toxicol Appl Pharmacol 1982;63:270-4.
Winge DR, Miklossy KA. Domain nature of metallothionein. J Biol Chem 1982;257:3471-6.
El-Maraghy SA, Rizk SM, El-Sawalhi MM. Hepatoprotective potential of crocin and curcumin against iron overload-induced biochemical alterations in rat. Afr J Biochem Res 2009;3:215-21.
Abd El-Baky A, Abdullah A, Abd-El Hay E. Amelioration of iron-overload adverse effect by iron chelator in rats. J Appl Sci Res 2009;5:1155-62.
Sarker R, Hazra B, Mandal N. Anti-oxidative protection against iron overload-induced liver damage in mice by Cajanuscajan (L.) Millsp. leaf extract. Indian J Exp Biol 2013;51:165-73.
Nematbakhsh M, Pezeshki Z, Moaeidi B, Eshraghi Jazi F, Talebi A, Nasri H, et al. Protective role of silymarin and deferoxamine against iron dextran induced renal iron deposition in male rats. Int J Prev Med 2013;4:286-92.
Nahdi A, Hammami I, Brasse-Lagnel C, Pilard N, Hamdaoui MH, Beaumont C, et al. Influence of garlic or its main active component diallyl disulfied on iron bioavailbility and toxicity. Nutr Res 2010;30:85-95.
Zhang Y, Li H, Zhao Y, Gao Z. Dietary supplementation of baicalin and quercetin attenuates iron overload induced mouse liver injury. Eur J Pharmacol 2006;535:263-9.
Limson J, Nyokong T, Daya S. The interaction of melatonin and its precursors with aluminium, cadmiun, copper, iron, lead and zincan adsorptive voltammetric study. J Pineal Res 1998;1:15-21.
Reiter RJ. Melatonin: lowering the high price of free radicals. News Physiol Sci 2000;15:246-50.
Flora SJS, Pant BP, Tripathi N, Kannan GM, Jaiswal DK. Therapeutic efficacy of a few diesters of meso 2,3-dimercaptosuccinic acid during sub-chronic arsenic intoxication in rats. J Occup Health 1997;39:119-23.
El-Sokkary GH, Abdel-Rahman GH, Kamel ES. Melatonin protects against lead-induced hepatic and renal toxicity in male rats. Toxicology 2005;213:25-33.
Kokoszko A, Dabrowski J, Lewiński A, Karbownik-Lewińska M. Protective effects of GH and IGF-I against iron-induced lipid peroxidation in vivo. Exp Toxicol Pathol 2008;60:453-8.
Ahmed MM, Ali SE. Protective effect of pomegranate peel ethanol extract against ferric nitrilotriacetate induced renal oxidative damage in rats. J Cell Mol Biol 2010;7/8:35-43.
Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12:1161-208.
Hou YJ, Zhao YY, Xiong B, Cui XS, Kim NH, Xu YX, et al. Mycotoxin-containing diet causes oxidative stress in the mouse. PLoS One 2013;8:e60374.
Garcia JJ, Reiter RJ, Ortiz GG, Oh CS, Tang L, Yu BP, et al. Melatonin enhances tamoxifen’s ability to prevent the reduction in microsomal membrane fluidity induced by lipid peroxidation. J Membr Biol 1998;162:59-65.
Tesoriere L, D’Arpa D, Conti S, Giaccone V, Pintaudi AM, Livrea MA. Melatonin protects human red blood cells from oxidative hemolysis: new insights into the radical scavenging activity. J Pineal Res 1999;27:95-105.
Jüngst C, Cheng B, Gehrke R, Schmitz V, Nischalke HD, Ramakers J, et al. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 2004;39:1663-72.
Whittaker P, Chanderbhan RF. Effect of increasing iron supplementation on blood lipids in rats. Br J Nutr 2001;86:587-92.
Manjunatha H, Srinivasan K. Protective effect of dietary curcumin and capsaicin on induced oxidation of low-density lipoprotein, iron-induced hepatotoxicity and carrageenan-induced inflammation in experimental rats. FEBS J 2006;273:4528-37.
Asare GA, Mossanda KS, Kew MC, Paterson AC, Kahler-Venter CP, Siziba K. Hepatocellular carcinoma caused by iron overload: A possible mechanism of direct hepatocarcinogenecity. Toxicology 2006;219:41-52.
Sylvain B, Louise T, Edgard D, Wagner Y, Moïse B, Emile L. Dietary iron overload and induced lipid peroxidation are associated with impaired plasma lipid transport and hepatic sterol metabolism in rats. Hepatology 2003;29:1809-17.
Foretz M, Foufelle F, Ferre´ P. Polyunsaturated fatty acids inhibit fatty acid synthase and spot-14-protein gene expression in cultured rat hepatocytes by a peroxidative mechanism. Biochem J 1999;341:371-6.
Brunet S, Thibault L, Delvin E, Yotov W, Bendayan M, Levy E. Dietary iron overload and induced lipid peroxidation are associated with impaired plasma lipid transport and hepatic sterol metabolism in rats. Hepatology 1999;29:1809-17.
Koppisetti S, Jenigiri B, Terron MP, Tengattini S, Tamura H, Flores LJ, et al. Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review. Dig Dis Sci 2008;53:2592-603.
Paulis L, Simko F. Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind. Physiol Res 2007;56:671-84.
Yasutake A, Hirayama K. Effects of iron overload on hepatic and renal metallothionein levels in rats. J Health Sci 2004;50:372-8.
Gūnther T, Grossrau R, Höllriegl V, Vormann J. Effects of Fe salicylate and Zn on metallothionein and lipid peroxidation in vivo. J Trace Elem Electrolytes Health Dis 1991;5:95-100.
Fleet JC, Andrews GK, McCormick CC. Iron-induced metallothionein in chick liver: rapid, rout-dependant effect independent of zinc status. J Nutr 1990;120:1214-22.
Kang YJ. Metallothionein redox cycle and function. Exp Biol Med 2006;231:1459-67.
Coyle P, Philcox JC, Carey LC, Rofe AM. Metallothionein: the multipurpose protein. Cell Mol Life Sci 2002;59:627-47.
Vasák M. Advances in metallothionein structure and functions. J Trace Elem Med Biol 2005;19:13-7.