Journal of Food and Nutrition Research
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Journal of Food and Nutrition Research. 2017, 5(1), 37-47
DOI: 10.12691/jfnr-5-1-7
Open AccessReview Article

Advantages of the Supplementation with both a Protein and Heme Hydrolyzate and Ionic Iron during Iron Deficiency Anemia

Yenela García1, , Olimpia Carrillo2, René Cárdenas3 and Javier Díaz-Castro4

1Laboratorio de Antianémicos y Nutracéuticos, Centro Nacional de Biopreparados (BioCen), Carretera Beltrán km 11/2, Mayabeque, Cuba

2Departamento de Bioquímica, Facultad de Biología, Universidad de la Habana, Cuba

3Departamento de Biología Celular. Facultad de Ciencias, Universidad Nacional autónoma de México (UNAM), México DF, México

4Departamento de Fisiología, Facultad de Farmacia, Universidad de Granada, España

Pub. Date: January 14, 2017

Cite this paper:
Yenela García, Olimpia Carrillo, René Cárdenas and Javier Díaz-Castro. Advantages of the Supplementation with both a Protein and Heme Hydrolyzate and Ionic Iron during Iron Deficiency Anemia. Journal of Food and Nutrition Research. 2017; 5(1):37-47. doi: 10.12691/jfnr-5-1-7


Background: nutritional anemia caused by iron (Fe) deficiency is considered a major public health problem. Interventions to address nutritional anemia have been traditionally focused on supplementation with ionic Fe that causes gastrointestinal adverse effects. On the other hand, some nutritional studies have demonstrated the advantages of supplementation with both, a protein and heme hydrolyzate and ionic Fe. However there are few experimental and clinical evidences to conclude on the efficacy of this supplementation strategy to treat the Fe deficiency and anemia. Aim: is to know about the physiological and biochemical events proposed to explain the anemia recovery during a treatment with both a protein and heme hydrolyzate and ionic Fe during Fe deficiency anemia recovery. Results: some aspects related to the most recent events elucidated about the metabolism of both chemical forms of Fe were included in this work. Nutritional supplements that exist from both, a protein hydrolyzate with heme and ionic Fe, with some results that demonstrate the efficacy of this treatment in humans and a rat model of anemia, are also discuss. Conclusion: supplementation with both Fe sources allows, simultaneously, the anemia recovery and the decreased oxidative damage caused by traditional Fe therapies to treat nutritional anemia by Fe deficiency.

anemia heme ionic Fe supplementation

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[1]  Abu-Ouf, N.M., Jan, M.M. “The impact of maternal iron deficiency and iron deficiency anemia on child’s health,” Saudi Medical Journal, 36(2).146-149.2015.
[2]  World Health Organization. Available: [Accessed Oct. 12, 2015].
[3]  Pita, G.M., Jiménez, S., Basabe B., García, R.G., Macías, C., Selva, L., Hernández, C., Cruz, M., Herrera, R., O’Farrill, R., Calderius, I., Paulí, K., Leyva, M., Arocha, C., Herrera, D. “Anemia in Children under Five Years Old in Eastern Cuba, 2005-2011,” MEDICC Review, 16 (1).16-23. 2014.
[4]  McLean, E., Egli, I., Cogswell, M., de Benoisand, B., Wojdyla, D. Worldwide prevalence of anemia in preschool aged children, pregnant women and non-pregnant women of reproductive age. In: Nutritional anemia, Sight and Life, Switzerland, 2007, 10-12.
[5]  Geissler, C., Singh, M. “Iron, Meat and Health,” Nutrients, 3. 283-316. 2011.
[6]  Milman, N. “Oral Iron Prophylaxis in Pregnancy: Not Too Little and Not Too Much!,” Journal of Pregnancy,1-8. 2012.
[7]  Venkatesh, M. The case for urgent action to address nutritional anemia. In: Nutritional anemia, Sight and Life Press, Switzerland, 2007, 13.
[8]  Khalafallan, A.A., Dennis, A.E. “Iron deficiency anemia in pregnancy and Postpartum: Pathophysiology and effect of oral versus intravenuos iron therapy,” Journal of Pregnancy, 2012 Available: [Accessed Feb. 1st, 2013].
[9]  Harrington, M., Hotz, C., Zeder, C., Polvo, G.O., Villalpando, S., Zimmermann, M.B., Walczyk, T., Rivera, J.A., Hurrell, R.F. “A comparison of the bioavailability of ferrous fumarate and ferrous sulfate in non-anemic Mexican women and children consuming a sweetened maize and milk drink,” European Journal Clinical Nutrition , 65. 20-25.2011.
[10]  Cancelo-Hidalgo, M.J., Castelo-Blanco, C., Palacios, S., Hava-Palazuelos, J., Ciria-Recasens, M., Manasanch, J., Pérez-Edo, L. “Tolerability of different oral iron supplements: a systematic review,” Current Medical Research Opinion, 29 (4).291-03. 2013.
[11]  González, R., Aznar, E., González, M., Hernández, J.C., Varela A., Silva, P., García, Y. “Nueva línea de productos para prevenir y tratar la anemia partiendo del hierro hemínico,”. Informacéutico, 15. 43-8. 2008.
[12]  Sobieraj, D. “Heme or non-heme? An overview of iron supplements,” DrugStore News, 2010. Available: [Accessed March 4, 2013].
[13]  Nagaraju, S.P., Cohn, A., Akbari, A., Davis, J.L., Zimmerman, L. “Heme iron polypeptide for the treatment of iron deficiency anemia in non-dialysis chronic kidney disease patient: a randomized controlled trial,” BMC Nephrology, 2013. Available: [Accessed May 28, 2013].
[14]  Vaghefi, N., Nedjaoum, F., Guillochon, D., Bureau, F., Arhan, P., Bougle, D. “Iron absorption from concentrated hemoglobin hydrolysate by rat,” Journal Nutrition of Biochemistry, 16. 347- 352. 2005.
[15]  Vaghefi, N., Nedjaoum, F., Guillochon, D., Bureau, F., Arhan, P., Bougle, D. “Influence of the extent of hemoglobin hydrolysis on the digestive absorption of heme iron. An in vitro study”, Journal Agriculture Food Chemistry, 50. 4969-73. 2002.
[16]  Arredondo, M., Kloosterman, J., Núñez, S., Segovia, F., Candia, V., Flores, S., Le Blanc, S., Olivares, M., Pizarro, F. “Heme iron uptake by Caco-2 cells is a saturable, temperature sentitive and modulated by extracellular pH and Potassium,” Biological Trace Elements Research, 125.109-19. 2008.
[17]  Layrisse, M., Martinez-Torres, C., Leets, I., Taylor, P., Ramirez, J. “Effect of histidine, cysteine, glutathione or beef on iron absorption in humans,” Journal Nutrition, 114. 217-23. 1984.
[18]  Conrad, M.E., Cortell, S., Williams, H.L., Foy, A.L. “Polymerizationand intraluminal factors in the absorption of hemoglobin iron,” Journal Laboratory and Clinical Medicine, 68. 659-668. 1966.
[19]  Hurrell, R.F. “Fortification: overcoming technical and practical barriers,” Journal of Nutrition, 132. 806S-812S. 2002.
[20]  Frykman, E., Bystrom, M., Jansson, U., Edberg, A., Hansen, T. “Side effects of iron supplements in blood donors: superior tolerance of heme iron,” Journal Laboratory and Clinical Medicine, 123. 561-64. 1994.
[21]  González, R., Pizarro, F., Aznar, E. “Biodisponibilidad del Fe en sujetos normales con el empleo de tres formulaciones farmacéuticas antianémicas,” Revista Mexicana de Ciencias Farmacéutica, 41 (Supl 1). 23. 2010.
[22]  Pizarro, F., Olivares, M., Hertrampf, E., Mazariegos, D.I., Arredondo, M., Letelier, A., Gidi, V. “Iron bis-glycine chelate competes for the non heme-iron absorption pathway,” American Journal Clinical Nutrition, 76: 577-81. 2002.
[23]  Campos, M.S., Pallares, D.I., Moratalla, A., Lopez-Aliaga, I., Gomez-Ayala, A.E., Hartiti, S., Alferez, M.J.M., Barrionuevo D.M., Lisbona, F. “Bioavailability of Fe, Ca, P and Mg in Fe deficient rats treated with different dietary iron,” Nutrition Research, 16 (4): 683-96. 1996.
[24]  Lisbona, F., Reyes, A.M., López-Aliaga, I., Barrionuevo, M., Alférez, M.J.M., Campos, M.S. “The importance of the proportion of heme/non heme iron in the diet to minimize the interference with calcium, phosphorus, and magnesium metabolism on recovery from nutritional ferropenic anemia,” Journal of Agriculture and Food Chemistry, 47. 2026-32. 1999.
[25]  Carpenter, C.E., Mahoney, A.W. “Contributions of heme and non heme iron to human nutrition,” Critical Review of Food Science and Nutrition, 31: 333-367. 1992.
[26]  Fritz, J.C., Pla, G.W., Roberts, T., Boehne, J.W., Hove, E.L. “Biological availability in animals of iron from common dietary sources,” Journal of Agriculture and Food Chemistry, 18: 647-51. 1970.
[27]  Conrad, M.E., Weintraub, L.R., Sears, D.A., Crosby, W.H. “Absorption of hemoglobin iron,” American Journal Physiology, 211. 1123-1130. 1966.
[28]  Gunshin, H., Mackenzie, B., Berger, U.V., Gunshin, Y., Romero, M.R., Boron, W.F., Nussberger, S., Gollan, J.L., Hediger, M.A. “Cloning and characterization of a mammalian proton coupled metal-ion transporter,” Nature, 388. 482-8. 1997.
[29]  McKie, A.T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., Miret, S., Bomford, A., Peters, T.J., Farzaneh, F., Hediger, M.A., Hentze, M.W., Simpson, R.J. “A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation,” Molecular Cell, 5. 299-309. 2000.
[30]  Hallberg, L., Rossander, L., Skanberg, A.B. “Phytates and the inhibitory effect of bran on iron absorption in man,” American Journal of Clinical Nutrition, 45. 988-96. 1987.
[31]  Siegenberg, D., Baynes, R.D., Bothwell, T.H., Macfarlane, B.J., Lamparelli, R.D., Car, N.G., MacPhail, P., Schmidt, U., Tal, A., Mayet, F. “Ascorbic acid prevents the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption,” American Journal of Clinical Nutrition, 53. 7-41. 1991.
[32]  Reddy, M.B., Hurrell, R.F., Juillerat, M.A., Cook, J.D. “The influence of different protein sources on phytate inhibition of nonheme-iron absorption in humans,” American Journal of Clinical Nutrition, 63.203-7. 1996.
[33]  Uzel, C., Conrad, M.E. “Absorption of heme iron,” Seminars in Hematology, 35. 27-34. 1998.
[34]  Gaitán, D., Flores, S., Saavedra, P., Miranda, C., Olivares, M., Arredondo, M., López de Romaña, D., Lonnerdal, B., Pizarro, F. “Calcium Does not inhibit the absorption of 5 milligrams of non heme or heme iron at doses less than 800 milligrams in non pregnant women,” Journal of Nutrition, 141(9). 1652-6. 2011.
[35]  McKie, A.T., Barrow, D., Latunde-Dada, G.O., Rolfs, A., Sager, G., Mudaly, E., Mudaly, M., Richardson, C., Barlow, D., Bomford, A., Peters, T.J., Raja, K.B., Shirali, S., Hediger, M.A., Farzaneh, F., Simpson, R.J. “An iron-regulated ferric reductase associated with the absorption of dietary iron,” Science 291.1755-9. 2001.
[36]  Gunshin, H., Starr, C.N., Direnzo, C., Fleming, M.D., Jin, J., Greer, E.L., Sellers, V.M., Galica, S.M., Andrews, N.C. “Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice,” Blood, 106(8). 2879-2883. 2005.
[37]  Knutson, M.D. “Steap proteins: implications for iron and copper metabolism,” Nutrition Review, 65(7). 335-340. 2007.
[38]  West, A.R., Oates, P.S. “Mechanisms of heme iron absorption: Current questions and controversies,” World Journal of Gastroenterology, 14 (26). 4101 - 10. 2008.
[39]  Roberts, S.K., Henderson, R.W., Young, G.P. “Modulation of uptake of heme by rat small intestinal mucosa in iron deficiency,” American Journal of Physiology, 265. G712-G718.1993.
[40]  Grasbeck, R., Kouvonen, I., Lundberg, M., Tenhunen, R. “An intestinal receptor for heme,” Scandinavian Journal of Haematology, 23. 5-9.1979.
[41]  Shayeghi, M., Latunde-Dada, G.O., Oakhill, J.S., Laftah, A.H., Takeuchi, K., Halliday, N., Khan, Y., Warley, A., MaCann, F.E., Hider, R.C., Frazer, D.M., Anderson, G.J., Vulpe, C.D., Simpson, R.J., Mackie, A.T. “Identification of an intestinal heme transporter,” Cell, 122. 789-801. 2005.
[42]  Qiu, A., Jansen, M., Sakaris, A., Min, S.H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M.H., Goldman, I.D. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell, 127. 917-928. 2006.
[43]  Le Blanc, S., Garrick, M.D., Arredondo, M. “Heme carrier protein 1 transports heme and is involved in heme-Fe metabolism,” American Journal of Physiology - Cell Physiology, 302: C1780–C1785. 2012.
[44]  Chiabrando, D., Vinchi, F., Fiorito, V., Mercurio, S., Tolosano, E. “Heme in pathophysiology: a matter of scavenging metabolism and trafficking across cell membranes,” Frontiers in Pharmacology, 5. 61. 2014.
[45]  Rajagopal, A., Rao, A.U., Amigo, J., Tian, M., Upadhyay, S.K., Hall, C., Uhm, S., Mathew, M.K., Fleming, M.D., Paw, B.H., Krause, M., Hamza, I. “Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins,” Nature, 453. 1127-1131. 2008.
[46]  Yanatori, I., Tabuchi, M., Kawai, Y., Yasui, Y., Akagi, R., Kishi, F. “Heme and non-heme iron transporters in non-polarized and polarized cells,” BMC Cell Biology, 11. 39. 2010.
[47]  White, C., Yuan, X., Schmidt, P.J., Bresciani, E., Samuel, T.K., Campagna, D., Hall, C., Bishop, K., Calicchio, M.L., Lapierre, A., Ward, D.M., Liu, P., Fleming, M.D., Hamza, I. “HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis,” Cell Metabolism, 17(2). 261-270. 2013.
[48]  Quigley, J.G., Yang, Z., Worthington, M.T., Phillips, J.D., Sabo, K.M., Sabath, D.E., Berg, C.L., Sassa, S., Wood, B.L., Abkowitz, J.L. “Identification of a human heme exporter that is essential for erythropoiesis,” Cell, 118(6). 757-766. 2004.
[49]  Keel, S.B., Doty, R.T., Yang, Z., Quigley, J.G., Chen, J., Knoblaugh, S., Kingsley, P.D., De Domenico, L., Vaughn, M.B., Kaplan, J., Palis, J., Abkowitz, J.L. “A heme export protein is required for red blood cell differentiation and iron homeostasis,” Science, 319(5864). 825-828. 2008.
[50]  Uc, A., Stokes, J.B., Britigan, B.E. “Heme transport exhibits polarity in Caco-2 cells: evidence for an active and membrane protein-mediated process,” American Journal of Physiology- Gastrointestinal and Liver Physiology, 287. G1150-7. 2004.
[51]  Chiabrando, D., Marro, S., Mercurio, S., Giorgi, C., Petrillo, S., Vinchi F, Fiorito, V., Fagoonee, S., Camporeale, A., Turco, E., Merlo, G.R., Silengo, L., Altruda, F., Pinton, P., Tolosano, E. “The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation,” The Journal of Clinical Investigation, 122. 4569-4579. 2012.
[52]  Yang, Z., Philips, J.D., Doty, R.T., Giraudi, P., Ostrow, J.D., Tiribelli, C., Smith, A., Abkowitz, J.L. “Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin,” Journal of Biologycal Chemistry, 285(37). 28874-28882. 2010.
[53]  Krishnamurthy, P., Ross, D.D., Nakanishi, T., Bailey-Dell, K., Zhou, S., Mercer, K.E., Sarkadi, B., Sorrentino, B.P., Schuetz, J.D. “The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme,” Journal of Biologycal Chemistry, 279. 24218-24225. 2004.
[54]  Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K., Ross, D.D. “A multidrug resistance transporter from human MCF-7 breast cancer cells,” Proceedings of the National Academy of Science of U.S.A., 95. 15665-15670. 1998.
[55]  Krishnamurthy, P., Schuetz, J.D. “The ABC transporter Abcg2/Bcrp: role in hypoxia mediated survival,” Biometals, 18(4). 349-58. 2005.
[56]  Latunde-Dada, G., Laftah, A.H., Masaratana, P., McKie, T., Simpson, R.J. “Expression of ABCG2 (BCRP) in mouse models with enhanced erythropoiesis,” Frontiers of Pharmacology, 5. 135. 2014.
[57]  Khan, A.A., Quigley, J.G. “Control of intracellular heme levels: Heme transporters and Hemeoxygenases,” Biochimica et Biophysica Acta, 1813 (5). 668-82. 2011.
[58]  Latude-Dada, G.O., Simpson, R.J., Mckie, A.T. Recent Advances in mammalian haem transport. Trends in Biochemical Sciences, 31 (3). 182-8. 2006.
[59]  Tenhunen, R., Marver, H.S., Schmidt, R.T. “The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase,” Proceedings of the National Academy of Science of U.S.A., 244. 6388-6394. 1968.
[60]  Tenhunen, R., Marver, H.S., Schmidt, R. “Microsomal Heme Oxygenase,” The Journal of Biological Chemistry, 244(23). 6388-94. 1969.
[61]  Maines, M.D. “Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications,” FASEB Journal, 2. 2557-2568. 1988.
[62]  Maines, M.D., Trakshel, G.M., Kurry, R.K. “Characterization of two constitutive forms of rat liver microsomal heme oxygenase: only one molecular species of the enzyme is inducible,” Journal of Biologycal Chemistry, 261. 411-419.1986.
[63]  Stocker, R., Yamamoto, Y., McDonagh, A.F., Glazer, A.N., Ames, B.N. “Bilirubin is an antioxidant of possible physiological importance,” Science, 235: 1043-1046. 1987.
[64]  Collins J.F., Franck, C.A., Kowdley, K.V., Ghishan, F.K. “Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum,” American Journal of Physiology- Gastrointestinal and Liver Physiology, 288. G964-G971. 2005.
[65]  Oates, P.S., West, A.R. “Heme in intestinal epithelial cell turnover, differentiation, detoxification, inflammation, carcinogenesis, absorption and motility,” World Journal of Gastroenterology, 12. 4281-4295. 2006.
[66]  West, A.R., Oates, P.S. “Subcellular location of heme oxygenase 1 and 2 and divalent metal transporter 1 in relation to endocytotic markers during heme iron absorption,” Journal of Gastroenterology and Hepatology, 23(1). 150-8. 2008.
[67]  Hentze, M.W., Muckenthaler, M.U., Andrews, N.C. “Balancing acts: molecular control of mammalian iron metabolism,” Cell, 117(3). 285-297. 2004.
[68]  Marx, J.M. “Mucosal uptake, mucosal transfer and retention of iron, measured by whole-body counting,” Scandinavian Journal of Haematology, 23. 293-302. 1979.
[69]  Anderson, G.J., Darshan, D., Wilkins, S.J., Frazer, D.M. “Regulation of systemic iron homeostasis: how the body responds to changes in iron demand,” Biometals, 20 (3-4). 665-674. 2007.
[70]  Conrad, M.E., Weintraub, L.R., Crosby, W.H. “The role of the intestine in iron kinetics,” Journal of Clinical Investigation, 43. 963-974. 1964.
[71]  Sharp, P.A. “Intestinal iron absorption: regulation by dietary & systemic factors,” International Journal for Vitamin and Nutrition Research, 80(4-5). 231-242. 2010.
[72]  Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., Ganz, T., Kaplan, J. “Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization,” Science, 306(5704). 2090-2093. 2004.
[73]  Laftah, A.H., Ramesh, B., Simpson, R.J., Solanky, N., Bahram, S., Schu¨mann, K., Debnam, E.S., Surjit, K., Srai, S., Ganz, T., Nemeth, E. “Effect of hepcidin on intestinal iron absorption in mice,” Blood, 103. 3940-3944. 2004.
[74]  Nemeth, E., Ganz, T. “Regulation of iron metabolism by hepcidin,” Annual Review of Nutrition, 26: 323-42. 2006.
[75]  Brasse-Lagnel, C., Karim, Z., Letteron, P., Bekri, S., Bado, A., Beaumont, C. “Intestinal DMT1 cotransporter is down-regulated by hepcidin via proteasome internalization and degradation,” Gastroenterology, 140(4). 1261-71. 2011.
[76]  Cao, C., Thomas, C.E., Insogna, K.I., O´Brien, K.O. “Duodenal absorption and tissue utilization of dietary heme and non heme iron differ in rat,” Journal of Nutrition, 144. 1710-1717. 2014.
[77]  Muckenthaler, M., Gray, N.K., Hentze, M.W. “IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F,” Molecular Cell, 2. 383-388. 1998.
[78]  Anderson, G.J., Frazer, D.M., McLaren, G.D. “Iron absorption and iron metabolism,” Current Opinion in Gastroenterology, 25. 129-135. 2009.
[79]  Muñoz, M., Villar, I., García-Erce, J.A. “An update on iron physiology,” World Journal of Gastroenterology, 15 (37). 4617-4626. 2009.
[80]  Abbaspour, N., Hurrell, R., Kelishadi, R. “Review on iron and its importance for human health,” Journal of Research in Medical Science, 19 (2). 164-174. 2014.
[81]  Fuqua, B.K., Lu, Y., Darshan, D., Frazer, D.M., Wilkins, S.J. , Wolkow, N, Bell, A.G., Hsu J.A., Yu, C.C., Chen, H., Dunaief, J.L., Anderson, G.J., Vulpe, C.D. “The Multicopper Ferroxidase Hephaestin Enhances Intestinal Iron Absorption in Mice,” PLoS One, 9(6). e98792. 2014.
[82]  Baker, H.M., Anderson, B.F., Naker, E.N. “Dealing with iron: common structural principles in proteins that transport iron and heme,” Proceedings of the National Academy of Science of U.S.A., 100. 3579-3583. 2003.
[83]  Cheng, Y., Zak, O., Aisen, P., Harrison, S.C., Walz, T. “Structure of the human transferrin receptor-transferrin complex,” Cell, 116. 565-576. 2004.
[84]  Kawabata, H., Yang, R., Hirama, T., Vuong, P.T., Kawano, S., Gom, Cassabart, A.F., Koeffler, H.P. “Molecular cloning of transferring receptor 2. A new member of the transferrin receptor-like family,” The Journal of Bioogical Chemistry, 274. 20826-20832. 1999.
[85]  Paoli, M., Anderson, B.F., Baker, H.M., Morgan, W.T., Smith, A., Baker, E.N. “Crystal structure of hemopexin reveals a novel high-affinity heme site formed between two b-propeller domains,” Nature Structural and Molecular Biology, 6. 926-931. 1999.
[86]  De Domenico, I., McVey Ward, D., Kaplan, J. “Regulation of iron acquisition and storage: consequences for iron-linked disorders,” Nature Reviews Molecular Cell Biology, 9. 72-81. 2008.
[87]  Schultz, I.J., Chen, C., Paw, B.H., Hamza, I. “Iron and Porphyrin Trafficking in heme biogenesis,” Journal of Biological Chemistry, 85 (35). 26753-59. 2010.
[88]  Yuan, X., Protchenko, O., Philpott, C.C., Hamza, I. “Topologically conserved residues direct heme transport in HRG-1 related proteins,” Journal of Biological Chemistry, 287(10). 4914-24. 2012.
[89]  Bratosin, D., Mazurier, J., Tissier, J.P., Estaquier, J., Huart, J.J., Ameisen, J.C., Aminoff, D., Montreuil, J. “Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review,” Biochimie, 80.173-195. 1998.
[90]  Mukhopadhyay, A., Bhatla, N., Kriplani, A., Pandey, R.M., Saxena, R. “Daily versus intermittent iron supplementation in pregnant women: Hematological and pregnancy outcome,” Journal of Obstetrics and Gynaecology Research, 30(6). 409-13. 2004.
[91]  Kumar, N., Chandhiok, N, Dhillon, B.S., Kumar, P. “Role of oxidative stress while controlling iron deficiency anemia during pregnancy - indian scenario,” Indian Journal of Clinical Biochemistry, 24 (1). 5-14. 2009.
[92]  Prousek, J. “Fenton chemistry in biology and medicine,” Pure and Applied Chemistry, 79. 2325-2338. 2007.
[93]  Zastawny, T.H., Altman, S.A., Randerseichhorn, L., Madurawe, R., Lumpkin, J.A., Dizdaroglu, M., Rao, G. “DNA base modifications and membrane damage in cultured mammalian cells treated with iron ions,” Free Radical Biology and Medicine, 18. 1013-1022. 1995.
[94]  Traber, M.G., Kamal-Eldin, A. Oxidative stress and vitamin E in anemia. In: Nutritional anemia, Sight and Life, Switzerland, 2007, 186.
[95]  Masella, R., Di Benedetto, R., Vari, R., Filesi, C., Giovannini, C. “Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related-enzymes,” The Journal of Nutritional Biochemistry, 16. 577-586. 2005.
[96]  Iwasaki, K., Hailemariam, K., Tsuji, Y. “PIAS3 interacts with ATF1 and regulates the human ferritin H gene through and Antioxidant Response Element,” Journal of Biological Chemistry, 282 (31). 22335-43. 2007.
[97]  Varady, J., Elder, K., Ringseis, R. “Dietary oxidized fat activates the oxidative stress-responsive transcription factor NF-κB and Nrf2 in intestinal mucosa of mice,” European Journal of Nutrition, 50 (8). 601-9. 2011.
[98]  Gessner, D.K., Fiesel, A., Most, E., Dinges, J., Wen, G., Ringseis, R., Eder, K. “Supplementation of a grape seed and grape marc meal extract decreases activities of the oxidative stress-responsive transcription factors NF-κB and Nrf2 in the duodenal mucosa of pigs,” Acta Veterinaria Scandinavica, 55. 1-10. 2013.
[99]  Jeney, V., Balla, J., Yachie, A., Varga, Z., Vercellotti, G.M, Eaton, J.W., Balla, G. “Pro-oxidant and cytotoxic effects of circulating heme,” Blood, 100(3). 879-87. 2002.
[100]  Kumar, S., Bandyopadhyay, U. “Free heme toxicity and its detoxification systems in human,” Toxicology Letters, 157(3). 175-88. 2005.
[101]  European Food Safety Authority. “Scientific Opinion on the safety of heme iron (blood peptonates) for the proposed uses as a source of iron added for nutritional purposes to foods for the general population, including food supplements,” EFSA Journal, 8(4).1585. 2010.
[102]  WHO Collaborating Centre for Drug Statistics Methodology, Norwegian institute of public health. “B03AE Iron in other combinations,” Available: [Accessed March 11, 2016].
[103]  Aznar, E., González, R., González, M., Suárez, S. Utilización del Trofin, NeoTrofin y sus formulaciones con vitamina C y ácido fólico para disminuir la anemia por deficiencia de hierro. In: Alimentación, Nutrición y Salud, MINSAP, La Habana. 2009. 173-75.
[104]  García, Y., González, R., García, A., Ángeles, S., Carmona, A., Cárdenas, R. “Efecto de la suplementación con diferentes fuentes de hierro durante la recuperación de ratas anémicas,” Revista CNIC Ciencias Biológicas, 44(3). 14-22. 2013.
[105]  Subcommittee on Laboratory Animal Nutrition. Nutrient Requirements of laboratory rat. In: Nutrient Requirements of laboratory animals. Academy Press, United States. 1995. 11-79.
[106]  Nadadur, S.S., Srirama, K., Mudipalli, A. “Iron transport and homeostasis mechanisms: Their role in health and diseases,” Indian Journal of International Medical Research, 128. 533-544. 2008.
[107]  García, Y., Díaz-Castro, J., López-Aliaga, I., Alférez, M.J.M., Ramos, A., Campos, M.S. “Bioavailability of Fe, Cu and Zn and antioxidant defense in anemic rat supplemented with a mixture of heme/non heme Fe,” Journal of Food and Nutrition Research, 52(2). 128-138. 2013.
[108]  Mastrogiannaki, M., Matak, P., Peyssonnaux, C. “The gut in the iron homeostasis: role of HIF-2 under normal and pathological conditions,” Blood, 122. 885-92. 2013.
[109]  Díaz-Castro, J., García, Y., López-Aliaga, I., Alférez, J.M., Hijano, S., Ramos, A., Campos, M.S. “Influence of Several Sources and Amounts of Iron on DNA, Lipid and Protein Oxidative Damage During Anaemia Recovery,” Biological Trace Element Research, 155. 403-410. 2013.
[110]  Thomas, C., Gaffney-Stomberg, E., Ben-Hua, S., O-Brien, K., Kerstetter, J., Insogna, K. “Increasing dietary protein acutely augments intestinal iron transporter expression and significantly increases iron absorption in rats,” FASEB Journal, 27. 2476-2483. 2013.
[111]  Miao, L., Clair, D.K. “Regulation of Superoxide Dismutase Genes: Implications in Diseases,” Free Radical Biology and Medicine, 47 (4). 344 -56. 2009.
[112]  Gasche, C., Lomer, M., Cavill, I., Weiss, G. “Iron, anaemia, and inflammatory bowel diseases,” Gut, 53: 1190-1197. 2004.
[113]  Gardner, L.C., Cox, T.M. “Biosynthesis of heme in immature erythroid cells,” Journal of Biological Chemistry, 263 (14). 6676-82. 1987.
[114]  Glueck, R., Green, D., Cohen, I., Ts´ao, C.H. “Hematin: unique effects of hemostasis,” Blood, 61. 243-249. 1983.
[115]  Tenhunen, R., Tokola, O., Lindén, I.B. “Haem arginate: a new stable haem compound,” Journal of Pharmacy and Pharmacology, 39 (10). 780-6. 1987.
[116]  Siegert, S.W., Holt, R.J. “Physicochemical properties, pharmacokinetics, and pharmacodynamics of intravenuos hematin: a literatura review,” Advances in Therapy, 25(9). 842- 57. 2008.
[117]  Yuan, X., Protchenko, O., Philpott, C.C., Hamza, I. “Topologically conserved residues direct heme transport in HRG-1 related proteins,” The Journal Biological Chemistry, 287(10). 4914-24. 2012.