The Role of Mangiferin in the Prevention of Experimentally Induced Iron Overload in an Animal Model

Abstract

Background The leaves, fruit peels, and bark of mango trees (Mangifera indica L) contain mangiferin as an active compound with known anti-oxidative and iron chelating properties. This study aims to evaluate the benefits of mangiferin in the management of iron overload.

Methods Thirty rats were divided into five groups: normal control, rats with iron overload, and rats with iron overload treated with oral mangiferin doses of 50, 100, or 200 mg/kg BW, respectively. The iron overload in this rat model was induced by means of 15 mg intraperitoneal iron dextran, twice a week for 4 weeks. Plasma mangiferin was measured using high performance liquid chromatography, plasma ferritin by using enzyme linked immunosorbent assay, and iron contents of plasma, urine, and tissues by using atomic absorbance spectrophotometry.

Results Plasma mangiferin concentration at doses of 50, 100, or 200 mg/kg BW were 416.10±112.04, 310.55±134.18, and 450.11±165.99 ng/mL, respectively. At 50 mg/kg BW, mangiferin significantly decreased plasma ferritin levels (from 7051.14±1368.24 to 5543.80±1225.53 ng/mL, (p=0.037). Mangiferin also showed tendency to increase urinary iron excretion and to decrease cardiac and hepatic iron accumulation.

Conclusion In our model, oral administration of mangiferin showed non-linear pharmacokinetics and low bioavailability. At a dose of 50 mg/kg BW, mangiferin decreased plasma ferritin levels significantly. Mangiferin did not prevent the increase of plasma iron, although it exerted tendency to increase urinary iron excretion and to decrease iron accumulation in liver and heart.

Key words

mangiferin - iron overload - iron excretion - plasma ferritin - plasma iron concentration

• References

• 1 Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med 2012; 366: 348-359
• 2 Rund D, Rachmilewitz E. β-thalassemia. N.Eng J Med 2005; 353: 1135-1145
• 3 Higher doses (100 or 200 mg/kg BW) of mangiferin were generally not more effective than 50 mg/kg BW.
• 4 Data Unit Kerja Kelompok Hematologi-Onkologi, Agustus 2014
• 5 Udyaningsih-Freisleben SK, Kurniati V, Prasetyo PB. et al. Isolated erythrocyte membranes of transfusion-dependent and non-transfused thalassemia patients in Jakarta – investigated by electron paramagnetic resonance spectroscopy. BioFactors 2003; 19: 87-100
• 6 Lee R, Bithell TC, Foerster J. et al. Wintrobe’s clinical hematology: The thalassemias and related disorders. 9th ed. Philadelphia: Lea &Febiger; 1993: 1131
• 7 Farmaki K, Tzoumari I, Pappa C. Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications. Blood Cells, Molecules and Diseases 2011; 47: 33-40
• 8 Brittenham GM. Iron-chelating therapy for transfusional iron overload. N Engl J Med 2011; 364: 146-156
• 9 Byrns MC, Penning TM. Environmental toxicology: Carcinogens and heavy metals. In: Brunton LL, Chabner BA, Knollmann BC. (eds) The pharmacological basis of therapeutics. New York: McGraw Hill; 2011: 1875-1876
• 10 Wiria MSS. Logam Berat dan Antagonisnya. In: Setiabudy R, Gan S. Nafrialdi. (editors) Farmakologi dan Terapi. Edisi V. Jakarta: Balai Penerbit UI. Jakarta; 2011: 860-861
• 11 Aji DN, Silman C, Aryudi C. et al. Faktor-faktor yang berhubungandengankualitashiduppasien thalassemia mayor di Pusat Thalassemia DepartemenIlmuKesehatanAnak RSCM. Sari Pediatri 2009; 11: 85-89
• 12 Pardo-Andreu GL, Cavalheiro RA, Dorta DJ. et al. Fe(III) shifts the mitochondria permeability transition-eliciting capacity of mangiferin to protection of organelle. J PharmacolExp Ther 2007; 320: 646-653
• 13 Pardo-Andreau GL, Baldoquin CS, Gonzales RA. et al. Fe(III) improves antioxidant and cytoprotecting activities of mangiferin. EurJPharmacol 2006; 547: 31-36
• 14 Pardo-Andreu GL, Barrios MF, Curti C. et al. Protective effects of Mangifera indica L extract (Vimang), and its major component mangiferin, on iron induced oxidative damage to rat serum and liver. Pharmacol Res 2008; 57: 79-86
• 15 Pardo-Andreu GL, Sanchez-Baldoquin C, Avila-Gonzalez R. et al. Interaction of vimang (Mangifera indica L. Extract) with Fe(III) improves its antioxidant and cytoprotecting activity. Pharmacol Res 2006; 54: 389-395
• 16 Rodriguez J, Di Pierro D, Gioia M. et al. Effects of natural extract from Mangifera indica L, and its active compound, mangiferin, on energy state and lipid peroxidation of red blood cells. BiochimBiophysActa 2006 1760; 1333-1342
• 17 Leiro JM, Alvarez E, Arranz JA. et al. In vitro effects of mangiferin on superoxide concentrations and expression of the inducible nitric oxide synthase, tumour necrosis factor-α and transforming growth factor β-genes. BiochemPharmacol 2003; 65: 1361-1371
• 18 Estuningtyas A, Zwicker K, Wahyuni T. et al. Are mangiferin and mangiferin-containing plant extracts helpful for iron-loaded transfusion-dependent and non-transfusion-dependent thalassaemia patients?. Biomed Pharmacol J 2018; 11: 29-43
• 19 Wahyuni T. (2013) Pengaruh mangiferin dan ekstrak air daun Mangifera foetida L. sebagai zat pengkelat besi dan antioksidan secara in vivo pada tikus Sprague Dawley. (thesis) Faculty of Medicine, Universitas Indonesia, Jakarta (Indonesian). 2013
• 20 Papanastasiou DA, Vayenas DV, Vassilopoulos A. et al. Animal and in vitro models in human disease concentration of iron and distribution of iron and transferrin after experimental iron overload in rat tissues in vivo : Study of the liver, the spleen, the central nervous system and other organs. Pathol Res Pract 2000; 196: 47-54
• 21 Hou S, Wang F, Li Y. et al. Pharmacokinetic study of mangiferin in human plasma after oral administration. Food Chem 2012; 132: 289-294
• 22 Genway. Immunoperoxidase assay for determination of FERRITIN in rat samples. San Diego: 1-4
• 23 Dahlan MS. Statistik untuk Kedokteran dan Kesehatan. Ed.5. Jakarta: Salemba Medika; 2011
• 24 Lai L, Lin LC, Lin JH. et al. Pharmacokinetic study of free mangiferin in rats by microdialysis coupled with microbore high performance liquid chromatography and tandem mass spectrometry. J Chrom A 2003; 987: 367-374
• 25 Wang Z, Deng J, Wang Q. et al. Improvement in the solubility of mangiferin by HP-β- CD inclusion. Chin Trad Pat Med 2008; 30: 1123-1126
• 26 Freitas PG, Barbosa AF, Saraiva LA. et al. Mangiferin binding to serum albumin is non-saturable and induces conformational changes at high concentrations. J Lumin 2012; 132: 3027-3034
• 27 Porter JB. Practical management of iron overload. Br J Haematol 2001; 115: 239-252
• 28 Cai F, Sun L, Gao S. et al. An improved LC-MS/MS method for determination in rat plasma and its application in nonlinear pharmacokinetics. Pharmazie 2014; 69: 168-172
• 29 Kontoghiorghe CN, Kontoghiorghes GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with nontransfusion-dependentthalassemiasyndromes. Drug DesDevTher 2016; 10: 465-481
• 30 Taher AT, Porter JB, Kattamis A. et al. Efficacy and safety of iron- chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron- loaded patients with nontransfusion-dependent thalassemia syndromes. Drug Des Dev Ther 2016; 10: 4073-4078 (Letter)
• 31 Jiang DJ, Dai Z, Li YJ. Pharmacological effects of xanthones as cardiovascular protective agents. CardiovascDrugRev 2004; 22: 91-102