Skip to main content
Log in

Acute inhibition of iron bioavailability by zinc: studies in humans

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

Iron (Fe) and zinc (Zn) deficiencies constitute two of the most important nutritional and public health problems affecting developing countries. Combined supplementation or fortification with Zn and Fe are strategies that can be used to improve the Zn and Fe status of a population. However, there is concern about potential negative interactions between these two micronutrients due to a competitive binding to DMT1 and Zip14 transporter. Studies performed in humans have shown an inhibitory effect of Zn on Fe absorption when both minerals are given together as a solution in fasting conditions. We found that at low doses of iron (0.5 mg) the threshold for the inhibition of iron bioavailability was at a Zn:Fe wt/wt ratio ≥5.9:1, whereas at higher doses of Fe (10 mg) this inhibition occurred at 1:1 Zn:Fe wt/wt ratio. This differential response could be explained by the variation in the abundance of both cations as they compete for a limited number of shared transporters at the enterocyte. Conflicting results have been obtained when this interaction was studied in different food matrices. A negative interaction was not observed when Fe and Zn were provided in a composite hamburger meal, premature formula, human milk, or cow milk. A decrease on Fe absorption was observed in only 1 of 3 studies when Fe and Zn were supplied in wheat flour. The possibility of a negative interaction should be considered for supplementation or fortification programs with both microminerals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Abd Rashed A (2011) In vitro study to determine the effect of zinc on non-heme iron absorption. IJCRIMPH 3:354–368

    Google Scholar 

  • Arredondo M, Martínez R, Núñez MT, Ruz M, Olivares M (2006) Inhibition of iron and copper uptake by iron, copper and zinc. Biol Res 39:95–102

    Article  PubMed  CAS  Google Scholar 

  • Bolívar L, Olivares M, López de Romaña D, Pizarro F (2011) Efecto del zinc sobre la absorción de hierro de leche de vaca fortificada con hierro, zinc y ácido ascórbico (Effect of zinc on iron absorption from cow’s milk fortified with iron, zinc and ascorbic acid). Rev Chil Nutr 38 (Suppl 1):1135 (Abstract)

  • Crofton RW, Gvozdanovic D, Gvozdanovic S, Khin CC, Brunt PW, Mowat NA, Agget PJ (1989) Inorganic zinc and the intestinal absorption of ferrous iron. Am J Clin Nutr 50:141–144

    PubMed  CAS  Google Scholar 

  • Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal (2001) Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. J Nutr 131:2860–2865

    PubMed  CAS  Google Scholar 

  • Espinoza A, Le Blanc S, Olivares M, Pizarro F, Ruz M, Arredondo M (2011) Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA. Biol Trace Elem Res Nov 9. [Epub ahead of print]

  • Fischer-Walker C, Kordas K, Stoltzfus RJ, Black RE (2005) Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials. Am J Clin Nutr 82:5–12

    PubMed  Google Scholar 

  • Friel JK, Serfass RE, Fennessey PV, Miller LV, Andrews WL, Simmons BS, Downton GF, Kwa PG (1998) Elevated intakes of zinc in infant formulas do not interfere with iron absorption in premature infants. J Pediatr Gastroenterol Nutr 27:312–316

    Article  PubMed  CAS  Google Scholar 

  • Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG, Hainsworth LN, Umbreit JN, Conrad ME, Feng L, Lis A, Roth JA, Singleton S, Garrick LM (2003) DMT1: a mammalian transporter for multiple metals. Biometals 16:41–54

    Article  PubMed  CAS  Google Scholar 

  • Garrick MD, Singleton ST, Vargas F, Kuo HC, Zhao L, Knopfel M, Davidson T, Costa M, Paradkar P, Roth JA, Garrick LM (2006) DMT1: which metals does it transport? Biol Res 39:79–85

    Article  PubMed  CAS  Google Scholar 

  • Gunshin H, Mackenzie H, Berger U, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gallan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-couple metal-ion transporter. Nature 388:482–488

    Article  PubMed  CAS  Google Scholar 

  • Harris WR (1983) Thermodynamic binding constants of the zinc-human serum transferrin complex. Biochemistry 16:3920–3926

    Article  Google Scholar 

  • Harrison PM (1996) The ferritins: molecular properties, iron storage functions and cellular regulation. Biochim Biophys Acta 1275:161–203

    Article  PubMed  Google Scholar 

  • Herman S, Griffin IJ, Suwarti S, Ernawati F, Permaesih D, Pambudi D, Abrams SA (2002) Cofortification of iron-fortified flour with zinc sulfate, but not zinc oxide, decreases iron absorption in Indonesian children. Am J Clin Nutr 76:813–817

    PubMed  CAS  Google Scholar 

  • Hettiarachchi M, Liyanage C, Hilmers D, Griffin I, Abrams SA (2010) Changing the zinc: iron ratio in a cereal-based nutritional supplement has no effect on percent absorption of iron and zinc in Sri Lankan children. Brit J Nutr 103:1015–1022

    Article  PubMed  CAS  Google Scholar 

  • International Zinc Nutrition Consultative Group (IZiNCG) (2004) Technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull 25 (suppl 2):S94–204

    Google Scholar 

  • Iyengar V, Pullakhandam R, Nair KM (2009) Iron-zinc interaction during uptake in human intestinal Caco-2 cell line: kinetic analyses and possible mechanism. Indian J Biochem Biophys 46:299–306

    PubMed  CAS  Google Scholar 

  • Iyengar V, Pullakhandam R, Nair KM (2010) Dietary ligands as determinants of iron-zinc interactions at the absorptive enterocyte. J Food Sci 75:260–264

    Article  Google Scholar 

  • Kordas K, Stoltzfus RJ (2004) New evidence of iron and zinc interplay at the enterocyte and neural tissues. J Nutr 134:1295–1298

    PubMed  CAS  Google Scholar 

  • Lind T, Lonnerdal B, Stenlund H, Gamayanti IL, Ismail D, Seswandhana R, Persson LA (2003) A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. Am J Clin Nutr 77:883–890

    PubMed  CAS  Google Scholar 

  • Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ (2006) Zip14 (Slc39a14) mediates non transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA 103:13612–13617

    Article  PubMed  CAS  Google Scholar 

  • López de Romaña D, Salazar M, Hambidge KM, Penny ME, Peerson JM, Sian L, Krebs NF, Brown KH (2005). Iron absorption by Peruvian children consuming wheat products fortified with iron only or iron and one of two levels of zinc. Proceedings of FASEB Experimental Biology, San Diego, 2–6 April 2005 (Abstract 274.23)

  • McLean E, Egli I, Cogswell M, de Benoist B, Wojdyla D (2007) Worldwide prevalence of anemia in preschool aged children, pregnant women and non-pregnant women of reproductive age. In: Kraemer KZM (ed) Nutritional anemia. Sight and Life Press, Switzerland, pp 1–12

    Google Scholar 

  • Niereder W (1990) Ferritin: iron incorporation and release. Experientia 26:218–220

    Article  Google Scholar 

  • Nishiyama S, Inomoto T, Nakamura T, Higashi A, Matsuda I (1996) Zinc status relates to hematological deficits in women endurance runners. J Am Coll Nutr 15:359–363

    PubMed  CAS  Google Scholar 

  • Nishiyama S, Irisa K, Matsubasa T, Higashi A, Matsuda I (1998) Zinc status relates to hematological deficits in middle-aged women. J Am Coll Nutr 17:291–295

    PubMed  CAS  Google Scholar 

  • Nishiyama S, Kiwaki K, Miyazaki Y, Hasuda T (1999) Zinc and IGF-I concentrations in pregnant women with anemia before and after supplementation with iron and/or zinc. J Am Coll Nutr 18:261–267

    PubMed  CAS  Google Scholar 

  • O’Brien KO, Zavaleta N, Caulfield LE, Yang DX, Abrams SA (1999) Influence of prenatal iron and zinc supplements on supplemental iron absorption, red blood cell iron incorporation, and iron status in pregnant Peruvian women. Am J Clin Nutr 69:509–515

    PubMed  Google Scholar 

  • Olivares M, Pizarro F, Ruz M (2007a) Zinc inhibits nonheme iron bioavailability in humans. Biol Trace Elem Res 117:7–14

    Article  PubMed  CAS  Google Scholar 

  • Olivares M, Pizarro F, Ruz M (2007b) New insights about iron bioavailability inhibition by zinc. Nutrition 23:292–295

    Article  PubMed  CAS  Google Scholar 

  • Olivares M, Pizarro F, Gaitán D, Ruz M (2007c) Acute inhibition of iron absorption by zinc. Nutr Res 27:279–282

    Article  CAS  Google Scholar 

  • Olivares M, Wiedeman A, Pizarro F, López de Romaña D (2010) Efecto de dosis crecientes de zinc sobre la absorción de hierro de una leche fortificada con hierro (Effect of increasing doses of zinc on iron absorption from an iron-fortified milk). Rev Chil Pediatr 81:592 (Abstract)

  • Rossander-Hulten L, Brune M, Sandstrom B, Lonnerdal B, Hallberg L (1991) Competitive inhibition of iron absorption by manganese and zinc in humans. Am J Clin Nutr 54:152–156

    PubMed  CAS  Google Scholar 

  • Schultink W, Merzenich M, Gross R, Shrimpton R, Dillon D (1997) Effects of iron-zinc supplementation on the iron, zinc, and vitamin A status of anaemic pre-school children. Food Nutr Bull 18:311–316

    Google Scholar 

  • Tacnet F, Lauthier F, Ripoche P (1993) Mechanisms of zinc transport into pig small intestine brush border membrane vesicles. J Physiol 465:57–72

    PubMed  CAS  Google Scholar 

  • Tallkvist J, Bowlus CL, Lonnerdal B (2000) Functional and molecular responses of human intestinal Caco-2 cells to iron treatment. Am J Clin Nutr 72:770–775

    PubMed  CAS  Google Scholar 

  • Tandy S, Williams M, Leggett A, Lopez-Jimenez M, Dedes M, Ramesh B, Srai SK, Sharp P (2000) Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J Biol Chem 275:1023–1029

    Article  PubMed  CAS  Google Scholar 

  • Whittaker P (1998) Iron and zinc interactions in humans. Am J Clin Nutr 68:442S–446S

    PubMed  CAS  Google Scholar 

  • Wien EM, Glahn RP, Van Campen DR (1994) Ferrous iron uptake by rat duodenal brush border membrane vesicles: effects of dietary iron level and competing minerals (Zn+2, Mn+2, and Ca+2). J Nutr Biochem 5:571–577

    Article  CAS  Google Scholar 

  • Yamaji S, Tennant J, Tandy S, Williams M, Srai SKS, Sharp P (2001) Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells. FEBS Lett 507:41–137

    Article  Google Scholar 

  • Zhao N, Gao J, Enns CA, Knutson MD (2010) ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J Biol Chem 15(285):32141–32150

    Article  Google Scholar 

Download references

Acknowledgment

Supported by grants from the National Fund for Scientific & Technological Development (FONDECYT) 1100094, 1070665, and 1040879.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Manuel Olivares.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Olivares, M., Pizarro, F., Ruz, M. et al. Acute inhibition of iron bioavailability by zinc: studies in humans. Biometals 25, 657–664 (2012). https://doi.org/10.1007/s10534-012-9524-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-012-9524-z

Keywords

Navigation