Generic placeholder image

Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Review Article

Protective Effects of Curcumin against Iron-induced Toxicity

Author(s): Nastaran Moinipour, Mahdi Barati, Amirhossein Sahebkar*, Milad Iranshahy and Abolfazl Shakeri*

Volume 23, Issue 8, 2022

Published on: 14 January, 2022

Page: [1020 - 1027] Pages: 8

DOI: 10.2174/1389201022666210914122846

Price: $65


Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in some organs including the liver, glands, brain, heart, gastrointestinal tract and lung. Iron chelation therapy could be considered an effective approach for removing excess iron. Deferoxamine, deferiprone and deferasirox are three common iron chelators in clinical practice but cause several side effects. In this context, the use of curcumin, a dietary phytochemical derived from turmeric, as a natural and safe antioxidant with iron-chelating activity may be a useful strategy for the management of iron overload. This review focuses on the deleterious effect of iron accumulation in different organs of the body as well as the therapeutic potential of curcumin against iron-induced toxicity.

Keywords: Iron overload, curcumin, toxicity, antioxidant, chelation, phytochemical.

Graphical Abstract
Cornelis, P.; Wei, Q.; Andrews, S.C.; Vinckx, T. Iron homeostasis and management of oxidative stress response in bacteria. Metallomics, 2011, 3(6), 540-549.
[] [PMID: 21566833]
Ganz, T. Hepcidin in iron metabolism. Curr. Opin. Hematol., 2004, 11(4), 251-254.
[] [PMID: 15314524]
Aisen, P. Transferrin receptor 1. Int. J. Biochem. Cell Biol., 2004, 36(11), 2137-2143.
[] [PMID: 15313461]
Kirschner, R.E.; Fantini, G.A. Role of iron and oxygen-derived free radicals in ischemia-reperfusion injury. J. Am. Coll. Surg., 1994, 179(1), 103-117.
[PMID: 8019714]
Rouault, T.A. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol., 2006, 2(8), 406-414.
[] [PMID: 16850017]
Ganz, T.; Nemeth, E. Iron homeostasis in host defence and inflammation. Nat. Rev. Immunol., 2015, 15(8), 500-510.
[] [PMID: 26160612]
Winter, W.E.; Bazydlo, L.A.; Harris, N.S. The molecular biology of human iron metabolism. Lab. Med., 2014, 45(2), 92-102.
[] [PMID: 24868988]
Silva, B.; Faustino, P. An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim. Biophys. Acta, 2015, 1852(7), 1347-1359.
[] [PMID: 25843914]
Gujja, P.; Rosing, D.R.; Tripodi, D.J.; Shizukuda, Y. Iron overload cardiomyopathy: better understanding of an increasing disorder. J. Am. Coll. Cardiol., 2010, 56(13), 1001-1012.
[] [PMID: 20846597]
Crichton, R.R.; Wilmet, S.; Legssyer, R.; Ward, R.J. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J. Inorg. Biochem., 2002, 91(1), 9-18.
[] [PMID: 12121757]
Hultcrantz, R.; Ahlberg, J.; Glaumann, H. Isolation of two lysosomal populations from iron-overloaded rat liver with different iron concentration and proteolytic activity. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol., 1984, 47(1), 55-65.
[] [PMID: 6151288]
Bacon, B.R.; Healey, J.F.; Brittenham, G.M.; Park, C.H.; Nunnari, J.; Tavill, A.S.; Bonkovsky, H.L. Hepatic microsomal function in rats with chronic dietary iron overload. Gastroenterology, 1986, 90(6), 1844-1853.
[] [PMID: 3009259]
Bacon, B.R.; Park, C.H.; Brittenham, G.M.; O’Neill, R.; Tavill, A.S. Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload. Hepatology, 1985, 5(5), 789-797.
[] [PMID: 4029891]
Sharifi-Rad, J.; Rayess, Y.E.; Rizk, A.A.; Sadaka, C.; Zgheib, R.; Zam, W.; Sestito, S.; Rapposelli, S.; Neffe-Skocińska, K.; Zielińska, D.; Salehi, B.; Setzer, W.N.; Dosoky, N.S.; Taheri, Y.; El Beyrouthy, M.; Martorell, M.; Ostrander, E.A.; Suleria, H.A.R.; Cho, W.C.; Maroyi, A.; Martins, N. Turmeric and its major compound curcumin on health: bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front. Pharmacol., 2020, 11, 01021.
[] [PMID: 33041781]
Ghandadi, M.; Sahebkar, A. Curcumin: an effective inhibitor of interleukin-6. Curr. Pharm. Des., 2017, 23(6), 921-931.
[] [PMID: 27719643 ]
Ghasemi, F.; Shafiee, M.; Banikazemi, Z.; Pourhanifeh, M.H.; Khanbabaei, H.; Shamshirian, A.; Amiri Moghadam, S. ArefNezhad, R.; Sahebkar, A.; Avan, A.; Mirzaei, H. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol. Res. Pract., 2019, 215(10), 152556.
[] [PMID: 31358480]
Panahi, Y.; Ahmadi, Y.; Teymouri, M.; Johnston, T.P.; Sahebkar, A. Curcumin as a potential candidate for treating hyperlipidemia: A review of cellular and metabolic mechanisms. J. Cell. Physiol., 2018, 233(1), 141-152.
[] [PMID: 28012169]
Mortezaee, K.; Salehi, E.; Mirtavoos-mahyari, H.; Motevaseli, E.; Najafi, M.; Farhood, B.; Rosengren, R.J.; Sahebkar, A. Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy. J. Cell. Physiol., 2019, 234(8), 12537-12550.
[] [PMID: 29458218] []
Zahedipour, F.; Hosseini, S.A.; Sathyapalan, T.; Majeed, M.; Jamialahmadi, T.; Al-Rasadi, K.; Banach, M.; Sahebkar, A. Potential effects of curcumin in the treatment of COVID-19 infection. Phytother. Res., 2020, 34(11), 2911-2920.
[] [PMID: 27896883] []
Jankun, J.; Wyganowska-Świątkowska, M.; Dettlaff, K.; Jelińska, A.; Surdacka, A.; Wątróbska-Świetlikowska, D.; Skrzypczak-Jankun, E. Determining whether curcumin degradation/condensation is actually bioactivation (Review). Int. J. Mol. Med., 2016, 37(5), 1151-1158.
[] [PMID: 26985652]
Pietrangelo, A.; Gualdi, R.; Casalgrandi, G.; Montosi, G.; Ventura, E. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents. J. Clin. Invest., 1995, 95(4), 1824-1831.
[] [PMID: 7706489]
Pietrangelo, A. Mechanisms of iron hepatotoxicity. J. Hepatol., 2016, 65(1), 226-227.
[] [PMID: 26855173]
Whitsett, J.A.; Wert, S.E.; Weaver, T.E. Diseases of pulmonary surfactant homeostasis. Annu. Rev. Pathol., 2015, 10, 371-393.
[] [PMID: 25621661]
Kumar, A.; Abdelmalak, B.; Inoue, Y.; Culver, D.A. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. Lancet Respir. Med., 2018, 6(7), 554-565.
[] [PMID: 29397349]
Ghio, A.J.; Stonehuerner, J.G.; Richards, J.H.; Crissman, K.M.; Roggli, V.L.; Piantadosi, C.A.; Carraway, M.S. Iron homeostasis and oxidative stress in idiopathic pulmonary alveolar proteinosis: A case-control study. Respir. Res., 2008, 9(1), 10-17.
[] [PMID: 18215276]
MacIntyre, N.R. Tissue hypoxia: implications for the respiratory clinician. Respir. Care, 2014, 59(10), 1590-1596.
[] [PMID: 25161296]
Thompson, A.B.; Bohling, T.; Heires, A.; Linder, J.; Rennard, S.I. Lower respiratory tract iron burden is increased in association with cigarette smoking. J. Lab. Clin. Med., 1991, 117(6), 493-499.
[PMID: 2045717]
Wesselius, L.J.; Nelson, M.E.; Skikne, B.S. Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers. Am. J. Respir. Crit. Care Med., 1994, 150(3), 690-695.
[] [PMID: 8087339]
Philippot, Q.; Deslée, G.; Adair-Kirk, T.L.; Woods, J.C.; Byers, D.; Conradi, S.; Dury, S.; Perotin, J.M.; Lebargy, F.; Cassan, C.; Le Naour, R.; Holtzman, M.J.; Pierce, R.A. Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. PLoS One, 2014, 9(5), e96285-e96293.
[] [PMID: 24789352]
Morgan, J.W.; Anders, E. Chemical composition of earth, Venus, and Mercury. Proc. Natl. Acad. Sci. USA, 1980, 77(12), 6973-6977.
[] [PMID: 16592930]
Ghio, A.J.; Hilborn, E.D.; Stonehuerner, J.G.; Dailey, L.A.; Carter, J.D.; Richards, J.H.; Crissman, K.M.; Foronjy, R.F.; Uyeminami, D.L.; Pinkerton, K.E. Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect. Am. J. Respir. Crit. Care Med., 2008, 178(11), 1130-1138.
[] [PMID: 18723436]
Rubenfeld, G.D.; Caldwell, E.; Peabody, E.; Weaver, J.; Martin, D.P.; Neff, M.; Stern, E.J.; Hudson, L.D. Incidence and outcomes of acute lung injury. N. Engl. J. Med., 2005, 353(16), 1685-1693.
[] [PMID: 16236739]
Maffettone, C.; Chen, G.; Drozdov, I.; Ouzounis, C.; Pantopoulos, K. Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert. PLoS One, 2010, 5(4), e10163-e10173.
[] [PMID: 20405006]
Lui, G.Y.; Obeidy, P.; Ford, S.J.; Tselepis, C.; Sharp, D.M.; Jansson, P.J.; Kalinowski, D.S.; Kovacevic, Z.; Lovejoy, D.B.; Richardson, D.R. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol. Pharmacol., 2013, 83(1), 179-190.
[] [PMID: 23074173]
Ganz, T. Anemia of Inflammation. N. Engl. J. Med., 2019, 381(12), 1148-1157.
[] [PMID: 31532961]
Ganz, T.; Nemeth, E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematology (Am. Soc. Hematol. Educ. Program), 2011, 2011(1), 538-542.
[] [PMID: 22160086]
Adams, P.C.; Deugnier, Y.; Moirand, R.; Brissot, P. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology, 1997, 25(1), 162-166.
[] [PMID: 8985284]
Niederau, C.; Fischer, R.; Pürschel, A.; Stremmel, W.; Häussinger, D.; Strohmeyer, G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology, 1996, 110(4), 1107-1119.
[] [PMID: 8613000]
Tsushima, R.G.; Wickenden, A.D.; Bouchard, R.A.; Oudit, G.Y.; Liu, P.P.; Backx, P.H. Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload. Circ. Res., 1999, 84(11), 1302-1309.
[] [PMID: 10364568]
Pucheu, S.; Coudray, C.; Tresallet, N.; Favier, A.; de Leiris, J. Effect of iron overload in the isolated ischemic and reperfused rat heart. Cardiovasc. Drugs Ther., 1993, 7(4), 701-711.
[] [PMID: 8241014]
Zhai, Z.; Zou, P.; Liu, F.; Xia, Z.; Li, J. Ferroptosis is a potential novel diagnostic and therapeutic target for patients with cardiomyopathy. Front. Cell Dev. Biol., 2021, 9, 649045.
[] [PMID: 33869204]
Octavia, Y.; Tocchetti, C.G.; Gabrielson, K.L.; Janssens, S.; Crijns, H.J.; Moens, A.L. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol., 2012, 52(6), 1213-1225.
[] [PMID: 22465037]
Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev., 2004, 56(2), 185-229.
[] [PMID: 15169927]
Cheng, C-F.; Lian, W-S. Prooxidant mechanisms in iron overload cardiomyopathy. BioMed Res. Int., 2013, 2013, 740573-740581.
[] [PMID: 24350287]
Liu, P.; Olivieri, N. Iron overload cardiomyopathies: new insights into an old disease. Cardiovasc. Drugs Ther., 1994, 8(1), 101-110.
[] [PMID: 8086319]
Bartfay, W.J.; Dawood, F.; Wen, W.H.; Lehotay, D.C.; Hou, D.; Bartfay, E.; Luo, X.; Backx, P.H.; Liu, P.P. Cardiac function and cytotoxic aldehyde production in a murine model of chronic iron-overload. Cardiovasc. Res., 1999, 43(4), 892-900.
[] [PMID: 10615416]
Kattamis, C.; Ladis, V.; Tsoussis, D.; Kaloumenou, I.; Theodoridis, C. Evolution of glucose intolerance and diabetes in transfused patients with thalassemia. Pediatr. Endocrinol. Rev., 2004, 2(Suppl. 2), 267-271.
[PMID: 16462709]
Chatterjee, R.; Katz, M. Reversible hypogonadotrophic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload. Clin. Endocrinol. (Oxf.), 2000, 53(1), 33-42.
[] [PMID: 10931078]
Abdulzahra, M.S.; Al-Hakeim, H.K.; Ridha, M.M. Study of the effect of iron overload on the function of endocrine glands in male thalassemia patients. Asian J. Transfus. Sci., 2011, 5(2), 127-131.
[] [PMID: 21897589]
Bishop, G.M.; Robinson, S.R. Quantitative analysis of cell death and ferritin expression in response to cortical iron: implications for hypoxia-ischemia and stroke. Brain Res., 2001, 907(1-2), 175-187.
[] [PMID: 11430901]
Siesjö, B.K.; Agardh, C.D.; Bengtsson, F. Free radicals and brain damage. Cerebrovasc. Brain Metab. Rev., 1989, 1(3), 165-211.
[PMID: 2701375]
Rauhala, P.; Chiueh, C.C. Effects of atypical antioxidative agents, S-nitrosoglutathione and manganese, on brain lipid peroxidation induced by iron leaking from tissue disruption. Ann. N. Y. Acad. Sci., 2000, 899, 238-254.
[] [PMID: 10863543]
Gutteridge, J.M.; Halliwell, B. Free radicals in biology and medicine; Clarendon Press, 1985.
Zhang, Z.; Wei, T.; Hou, J.; Li, G.; Yu, S.; Xin, W. Iron-induced oxidative damage and apoptosis in cerebellar granule cells: attenuation by tetramethylpyrazine and ferulic acid. Eur. J. Pharmacol., 2003, 467(1-3), 41-47.
[] [PMID: 12706453]
Calabrese, V.; Lodi, R.; Tonon, C.; D’Agata, V.; Sapienza, M.; Scapagnini, G.; Mangiameli, A.; Pennisi, G.; Stella, A.M.; Butterfield, D.A. Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich’s ataxia. J. Neurol. Sci., 2005, 233(1-2), 145-162.
[] [PMID: 15896810]
Raps, S.P.; Lai, J.C.; Hertz, L.; Cooper, A.J. Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res., 1989, 493(2), 398-401.
[] [PMID: 2765907]
Oide, T.; Yoshida, K.; Kaneko, K.; Ohta, M.; Arima, K. Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia. Neuropathol. Appl. Neurobiol., 2006, 32(2), 170-176.
[] [PMID: 16599945]
Robb, S.J.; Robb-Gaspers, L.D.; Scaduto, R.C., Jr; Thomas, A.P.; Connor, J.R. Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes. J. Neurosci. Res., 1999, 55(6), 674-686.
[<674:AID-JNR3>3.0.CO;2-J] [PMID: 10220109]
Bar-Oz, B.; Levichek, Z.; Koren, G. Medications that can be fatal for a toddler with one tablet or teaspoonful: A 2004 update. Paediatr. Drugs, 2004, 6(2), 123-126.
[] [PMID: 15035652]
Goodwin, K.J.; Muegge, J.; Saltzman, D.A.; Acton, R.D.; Hess, D.J. Bowel perforation secondary to local tissue injury from intentional iron overdose. J. Pediatr. Surg. Case Rep., 2019, 50, 101301-101303.
Ben-Assa, E.; Youngster, I.; Kozer, E.; Abu-Kishk, I.; Bar-Haim, A.; Bar-Oz, B.; Berkovitch, M. Changes in serum hepcidin levels in acute iron intoxication in a rat model. Toxicol. Lett., 2009, 189(3), 242-247.
[] [PMID: 19524651]
Kwiatkowski, J.L. Real-world use of iron chelators. Hematology (Am. Soc. Hematol. Educ. Program), 2011, 2011, 451-458.
[] [PMID: 22160073]
Lebda, M. Acute Iron Overload and Potential Chemotherapeutic Effect of Turmeric in Rats. Int. J. Pure App. Biosci., 2014, 2, 86-94.
Mohammadi, E.; Tamaddoni, A.; Qujeq, D.; Nasseri, E.; Zayeri, F.; Zand, H.; Gholami, M.; Mir, S.M. An investigation of the effects of curcumin on iron overload, hepcidin level, and liver function in β-thalassemia major patients: A double-blind randomized controlled clinical trial. Phytother. Res., 2018, 32(9), 1828-1835.
[] [PMID: 29806132]
Kose, T.; Vera-Aviles, M.; Sharp, P.A.; Latunde-Dada, G.O. Curcumin and (-)- epigallocatechin-3-gallate protect murine MIN6 pancreatic beta-cells against iron toxicity and erastin-induced ferroptosis. Pharmaceuticals (Basel), 2019, 12(1), 26.
[] [PMID: 30736288]
Shakeri, A.; Sahebkar, A. ppinion paper: phytosome: a fatty solution for efficient formulation of phytopharmaceuticals. Recent Pat. Drug Deliv. Formul., 2016, 10(1), 7-10.
[] [PMID: 26268361]
Reddy, A.C.; Lokesh, B.R. Effect of curcumin and eugenol on iron-induced hepatic toxicity in rats. Toxicology, 1996, 107(1), 39-45.
[] [PMID: 8597030]
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(19), 4528-4537.
[] [PMID: 16956363]
Tamaddoni, A.; Nasseri, E.; Mohammadi, E.; Qujeq, D.; Zayeri, F.; Zand, H. A double-blind randomized controlled trial of curcumin for improvement in glycemic status, lipid profile and systemic inflammation in β-thalassemia major. J. Herb. Med., 2019, 100324.
Messner, D.J.; Robinson, T.; Kowdley, K.V. Curcumin and turmeric modulate the tumor-promoting effects of iron in vitro. Nutr. Cancer, 2017, 69(3), 481-489.
[] [PMID: 28129008]
Badria, F.A.; Ibrahim, A.S.; Badria, A.F.; Elmarakby, A.A. curcumin attenuates iron accumulation and oxidative stress in the liver and spleen of chronic iron-overloaded rats. PLoS One, 2015, 10(7), e0134156-e0134169.
[] [PMID: 26230491]
Sreejayan, Rao MNA. Curcumin inhibits iron-dependent lipid peroxidation. Int. J. Pharm., 1993, 100(1), 93-97.
Zoheb, S.M.; Prakash, A.; Rahal, A.; Mandil, R.; Gangwar, N.K.; Garg, S.K. Curcumin attenuates oxidative stress-induced altered histoarchitecture of testes in experimentally exposed rats to metal mixture (lead, arsenic, cadmium, mercury, iron, and copper) for 28 days. Environ. Toxicol. Chem., 2014, 96(4), 660-679.
Olsen, I. Porphyromonas Gingivalis May seek the alzheimer’s disease brain to acquire iron from its surplus. J. Alzheimers Dis. Rep., 2021, 5(1), 79-86.
[] [PMID: 33681719]
Baum, L.; Ng, A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer’s disease animal models. J. Alzheimers Dis., 2004, 6(4), 367-377.
[] [PMID: 15345806]
Jyoti, A.; Sethi, P.; Sharma, D. Curcumin protects against electrobehavioral progression of seizures in the iron-induced experimental model of epileptogenesis. Epilepsy Behav., 2009, 14(2), 300-308.
[] [PMID: 19100339]
Kumar, V.; Prakash, C.; Singh, R.; Sharma, D. Curcumin’s antiepileptic effect, and alterations in Nav1.1 and Nav1.6 expression in iron-induced epilepsy. Epilepsy Res., 2019, 150, 7-16.
[] [PMID: 30605865]
Dai, M.C.; Zhong, Z.H.; Sun, Y.H.; Sun, Q.F.; Wang, Y.T.; Yang, G.Y.; Bian, L.G. Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis. Neurosci. Lett., 2013, 536, 41-46.
[] [PMID: 23328441]
Matter, R.M.; Elbarbary, N.S.; Ismail, E.A.R.; Darwish, Y.W.; Nada, A.S.; Banoub, V.P. Zinc supplementation improves glucose homeostasis in patients with β-thalassemia major complicated with diabetes mellitus: A randomized controlled trial. Nutrition, 2020, 73, 110702-110729.
[] [PMID: 32007694]
Uzun, F.; Karaca, E.E.; Yıldız Yerlikaya, G.; Fındık, H.; Akın, M. Retinal nerve fiber layer thickness in children with β-thalassemia major. Saudi J. Ophthalmol., 2017, 31(4), 224-228.
[] [PMID: 29234223]
El-Shanshory, M.; Hablas, N.M.; Aboonq, M.S.; Fakhreldin, A.R.; Attia, M.; Arafa, W. Nigella sativa improves anemia, enhances immunity and relieves iron overload-induced oxidative stress as a novel promising treatment in children having beta-thalassemia major. J. Herb. Med., 2019, 16, 100245.
Sajadi Hezaveh, Z.; Azarkeivan, A.; Janani, L.; Hosseini, S.; Shidfar, F. The effect of quercetin on iron overload and inflammation in β-thalassemia major patients: A double-blind randomized clinical trial. Complement. Ther. Med., 2019, 46, 24-28.
[] [PMID: 31519283]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy