Abstract
In pathologic conditions or poisoning states, iron overload can affect different tissues including liver. In this study, the prophylactic effect of deferoxamine and silymarin was compared in decreasing experimental iron-overload-induced hepatotoxicity in rats. The study was done in six groups of rats, which received drugs q2 days for 2 weeks. The rats in groups 1 to 6 received drugs, respectively: normal saline, iron dextran, iron dextran + deferoxamine (intraperitoneally), iron dextran + silymarin (orally), iron dextran + silymarin (intraperitoneally), and iron dextran + deferoxamine (intraperitoneally) + silymarin (intraperitoneally). At the end of the study, blood was collected, and serum was separated for laboratory tests. The liver of rats was separated for iron measuring and tissue processing. The serum iron concentration and the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were determined. The numbers of necrotic hepatocytes were counted as quantity index tissue injury in light microscopic examination. The mean of serum and liver iron in group 2 was significantly greater than group 1. Liver iron was significantly decreased in other groups except group 4. Also serum iron was decreased in groups 3 to 6 compared to group 2 (nearly 400%). ALT activity in group 3 and AST activity in group 5 were significantly lesser than in other groups. The mean of necrotic hepatocytes in group 2 was significantly increased in comparison to group 1. This elevation was significantly prevented by deferoxamine and silymarin. The result of the present study shows that silymarin has a protective effect similar to deferoxamine on iron overload-induced hepatotoxicity.
Keywords: Silymarin, Deferoxamine, Iron overload, Rats, Hepatotoxicity
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Acknowledgment
The authors wish to express their gratitude to the research council of Shahid Chamran University for their financial support of present study.
References
- 1.Abu Ghadeer AR, Ali SE, Osman SA, Abu Bedair FA, Abbady MM, El-Kady MR. Antagonistic role of silymarin against cardiotoxicity and impaired antioxidant induced by adriamycin and/or radiation exposure in albino rats. Pakistan J Biol Sci. 2001;4:604–607. doi: 10.3923/pjbs.2001.604.607. [DOI] [Google Scholar]
- 2.Ahmed B, Khan SA, Alam T. Synthesis and antihepatotoxic activity of some heterocyclic compounds containing the 1, 4-dioxane ring system. Pharmazie. 2003;58:173–176. [PubMed] [Google Scholar]
- 3.Arezzini B, Lunghi B, Lungarella G, Gardi C. Iron overload enhances the development of experimental liver cirrhosis in mice. Int J Biochem Cell Biol. 2003;35:486–495. doi: 10.1016/S1357-2725(02)00298-4. [DOI] [PubMed] [Google Scholar]
- 4.Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-mediated process? Hepatol. 1990;11:127–137. doi: 10.1002/hep.1840110122. [DOI] [PubMed] [Google Scholar]
- 5.Bhattacharya A, Ramanathan M, Ghosal S, Bhattacharya SK. Effect of withania samra glycoeithanolides on iron-induced hepatotoxicity in rats. Phytother Res. 2000;14:568–570. doi: 10.1002/1099-1573(200011)14:7<568::AID-PTR663>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- 6.Borsari M, Gabbi C, Ghelfi F, Grandi R, Saladini M, Severi S, Borella F. Silybin, a new iron-chelating agent. J Inorg Biochem. 2001;85:123–129. doi: 10.1016/S0162-0134(01)00198-2. [DOI] [PubMed] [Google Scholar]
- 7.Chon SK, Kim NS. Evaluation of silymarin in the treatment on asymptomatic Giardia infections in dogs. Parasitol Res. 2005;97:445–451. doi: 10.1007/s00436-005-1462-z. [DOI] [PubMed] [Google Scholar]
- 8.Crocenzi FA, Sanchez Pozzi EJ, Pellegrino JM, Rodriguez Garay EA, Mottino AD, Roma MG. Preventive effect of silymarin against taurolithocholate-induced cholestasis in the rat. Biochem Pharmacol. 2003;66:355–364. doi: 10.1016/S0006-2952(03)00253-3. [DOI] [PubMed] [Google Scholar]
- 9.Dong JJ, Bauer M. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by down regulation of procollagen1 (I) and TIMP-1. J Hepatol. 2001;35:392–398. doi: 10.1016/S0168-8278(01)00148-9. [DOI] [PubMed] [Google Scholar]
- 10.Emerit J, Beaumont C, Trivin F. Iron metabolism, free radicals and oxidative injury. Biomed Pharmacother. 2001;55:333–339. doi: 10.1016/S0753-3322(01)00068-3. [DOI] [PubMed] [Google Scholar]
- 11.Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol. 1995;22:449–456. doi: 10.1016/0168-8278(95)80108-1. [DOI] [PubMed] [Google Scholar]
- 12.Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol. 1998;93(2):139–43. doi: 10.1111/j.1572-0241.1998.00139.x. [DOI] [PubMed] [Google Scholar]
- 13.George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterol. 1998;114:311–318. doi: 10.1016/S0016-5085(98)70482-2. [DOI] [PubMed] [Google Scholar]
- 14.George DK, Ramm GA, Powell LW, Fletcher LM, Walker NI, Cowley LL, Crawford DH. Evidence for altered hepatic matrix degradation in genetic haemochromatosis. Gut. 1998;42:715–720. doi: 10.1136/gut.42.5.715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Hakova H, Misurova E, Kropacova R. The effect of silymarin on the concentration and total content of nucleic acids in tissues of continuously irradiated rats. Vet Med (Praha) 1996;41:113–119. [PubMed] [Google Scholar]
- 16.Houglum K, Filip M, Josephl W, Chojkier M. Malondialehyde and 4-hydroxyno nenal protein adducts in plasma and liver of rats with iron overloads. J Clinic Investig Inc. 1990;86:1991–1998. doi: 10.1172/JCI114934. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Jensen PD, Jensen FT, Christensen T, Nielsen JL, Ellegaard J. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood. 2003;101(1):91–96. doi: 10.1182/blood-2002-06-1704. [DOI] [PubMed] [Google Scholar]
- 18.Kadikoylu G, Bolaman Z, Demir S, Balkaya M, Akalin N, Enli Y. The effects of desferrioxamine on cisplatininduced lipid peroxidation and the activities of antioxidant enzymes in rat kidneys. Hum Exp Toxicol. 2004;23:29–34. doi: 10.1191/0960327104ht413oa. [DOI] [PubMed] [Google Scholar]
- 19.Kang JS, Jeon YJ, Park SK, Yang KH, Kim HM. Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1 beta and prostaglandin E2 synthesis by silymarin. Biochem Pharmacol. 2004;67:175–181. doi: 10.1016/j.bcp.2003.08.032. [DOI] [PubMed] [Google Scholar]
- 20.Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, Kolnagou A. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1) Transfus Sci. 2000;23:211–223. doi: 10.1016/S0955-3886(00)00089-8. [DOI] [PubMed] [Google Scholar]
- 21.Laekeman G, De Coster S, De Meyer K, Leuven KU. St. Mary’s Thistle: an overview. J Pharm Belg. 2003;58:28–31. [PubMed] [Google Scholar]
- 22.Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterol. 1997;112:882–888. doi: 10.1053/gast.1997.v112.pm9041250. [DOI] [PubMed] [Google Scholar]
- 23.Mayers M, Brent G, Prendergast F, Holman R, Kuntz S, Larusso N. Alterations in the structure, physiochemical properties, and pH of hepatocyte lysosomes in experimental iron overload. J Clin Invest Inc. 1991;88:1207–1215. doi: 10.1172/JCI115423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs. 2005;65:2445–2461. doi: 10.2165/00003495-200565170-00003. [DOI] [PubMed] [Google Scholar]
- 25.Mereish KA, Bunner DL, Regland DR, Creasia DA. Protection against microcystin-L. R. induced hepatotoxicity by silymarin: biochemistry, histopathology and lethality. Pharmacol Res. 1991;8:257–277. doi: 10.1023/a:1015868809990. [DOI] [PubMed] [Google Scholar]
- 26.Mira L, Silva M, Manso CF. Scavenging of reactive oxygen species by silibin dihemisuccinate. Biochem Pharmacol. 1994;48:753–759. doi: 10.1016/0006-2952(94)90053-1. [DOI] [PubMed] [Google Scholar]
- 27.Naveau S. Acute alcoholic hepatitis treatments. Press Med. 2001;30:1024–1030. [PubMed] [Google Scholar]
- 28.Oliveira C, Lopasso FP, Laurindo F, Leitao R, Laundanna AA. Protection against liver ischemia–reperfusion injury in rats by silymarin or verapamil. Transplant Proc. 2001;33:3010–3014. doi: 10.1016/S0041-1345(01)02288-6. [DOI] [PubMed] [Google Scholar]
- 29.Peretz G, Link G, Pappo O, Bruck R, Ackerman Z. Effect of hepatic iron concentration reduction on hepatic fibrosis and damage in rats with cholestatic liver disease. World J Gastroenterol. 2006;12(2):240–245. doi: 10.3748/wjg.v12.i2.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis. 1996;16:13–30. doi: 10.1055/s-2007-1007215. [DOI] [PubMed] [Google Scholar]
- 31.Poli G, Parola M. Oxidative damage and fibrogenesis. Free Radic Biol Med. 1997;22:287–305. doi: 10.1016/S0891-5849(96)00327-9. [DOI] [PubMed] [Google Scholar]
- 32.Ramadan L, Roushdy HM, Abu Senna GM, Amin NE, El-Deshw OA. Radioprotectve effect of silymarin against radiation induced hepatotoxicity. Pharmacol Res. 2002;45:447–452. doi: 10.1006/phrs.2002.0990. [DOI] [PubMed] [Google Scholar]
- 33.Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver disease. Drugs. 2001;61(4):2034–2061. doi: 10.2165/00003495-200161140-00003. [DOI] [PubMed] [Google Scholar]
- 34.Soto C, Recoba R, Barron H, Alvarez C, Favari L. Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas. Comp Biochem Physiol C Toxicol Pharmacol. 2003;136:205–212. doi: 10.1016/S1532-0456(03)00214-X. [DOI] [PubMed] [Google Scholar]
- 35.Valenzuela A, Monica A, Soledad V, Ricardo G. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rats. Planta Med. 1989;55:420–422. doi: 10.1055/s-2006-962056. [DOI] [PubMed] [Google Scholar]
- 36.Varzi NH, Esmailzadeh S, Morovvati H, Avizeh R, Shahriari A, Givi EM. Effect of silymarin and vitamin E on gentamicin-induced nephrotoxicity in dogs. J Vet Pharmacol Ther. 2007;30:477–481. doi: 10.1111/j.1365-2885.2007.00901.x. [DOI] [PubMed] [Google Scholar]
- 37.Vladimir K, Daniela W. Silybin and silymarin—new effects and applications. Biomedical Papers. 2005;149:29–41. doi: 10.5507/bp.2005.002. [DOI] [PubMed] [Google Scholar]
- 38.Whittaker P, Hines FA, Robl MG, Dunkel VC. Histopathological evaluation of liver, pancreas, spleen, and heart from iron-overloaded Sprague–Dawley rats. Toxicol Pathol. 1996;24(5):558–563. doi: 10.1177/019262339602400504. [DOI] [PubMed] [Google Scholar]
- 39.Zhao Y, Li H, Gao Z, Xu H. Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. Europ J Pharmacol. 2005;509(2–3):195–200. doi: 10.1016/j.ejphar.2004.11.060. [DOI] [PubMed] [Google Scholar]