Computational study of metal complexes formed with EDTA, melatonin, and its main metabolites: implications in lead intoxication and clues to a plausible alternative treatment

  • Erik Díaz-Cervantes
  • Marco A. García-Revilla
  • Karla Soto-Arredondo
  • Tayde Villaseñor-Granados
  • Minerva Martínez-Alfaro
  • Juvencio RoblesEmail author
Original Paper


Melatonin has been proposed as an alternative treatment to the usage of EDTA for lead intoxication. In this computational paper, since previous work has not systematically studied the complexes that may be formed in the existing and proposed treatments, we study 45 possible complexes that we suggest may be formed between Pb and some essential metals with melatonin, melatonin metabolites, and EDTA, analyzing the stability and viability of these through the Gibbs free energy of complexation (ΔΔG), molecular orbitals, and energy decomposition analysis at the DFT level of theory PBE/TZ2P. Our findings show that most complexes present exergonic energies of reaction, and thus spontaneous complex formation. In addition, we show that the AMK and 3OHM melatonin metabolites possess electronic and thermodynamic properties adequate to act as lead trapping molecules due to the lower Pauli repulsion energies involved in the complexes they form and their large negative values of ΔΔG. Therefore, it is shown that both melatonin and some of its metabolites may be employed in a viable treatment for lead intoxication through formation of stable Pb-complexes.

Graphical abstract

Metal complexes formed with EDTA, melatonin, and its main metabolites


Melatonin DFT AMK AFMK 3OHM Pb-complexes 



E. Díaz-Cervantes and Karla Soto-Arredondo acknowledge support from a postdoctoral scholarship from Universidad de Guanajuato (Fortalecimiento de la excelencia académica 2015). We are all grateful to the Laboratorio Nacional de Caracterización de Propiedades Fisicoquímicas y Estructura Molecular (UG-UAA-CONACYT, Project: 123732) for the computing time provided. JR gratefully acknowledges financial support from the “Convocatoria Institucional de Apoyo a la Investigación Científica 2016-2017” from the UG, project No. 736/2016. We are thankful to Prof. Alberto Flores for helpful discussions.

Authors’ contribution

E. Díaz-Cervantes

Performed DFT calculations and writing.

M. A. García-Revilla

Performed DFT calculations.

K. Soto-Arredondo

Discussion and ideas from experimental toxicology lab.

T. Villaseñor-Granados

Performed DFT calculations.

M. Martínez-Alfaro

Discussion and ideas from experimental toxicology lab.

J. Robles

General discussion, integration and writing the manuscript.


  1. 1.
    Waldron HA (1966) Br J Ind Med 23:83–100PubMedPubMedCentralGoogle Scholar
  2. 2.
    Laggett RW (1993) Environ Health Perspect 101:598–616CrossRefGoogle Scholar
  3. 3.
    Lihm H, Kim H, Chang H, Yoon M, Lee K, Choi J (2013) Vitamin C modulates lead excretion in rats. Anat Cell Biol 46:239–245CrossRefGoogle Scholar
  4. 4.
    Chisolm JJ (1968) J Pediatr 73:1–38CrossRefGoogle Scholar
  5. 5.
    Andersen O, Aaseth J (2016) J Trace Elem Med Biol 38:74–80CrossRefGoogle Scholar
  6. 6.
    Martínez-Alfaro M, Hernandez-Cortes D, Wrobel K, Cruz-Jimenez G, Rivera-Leyva JC, Pina-Zentella RM, Carabez-Trejo A (2012) Mutat Res 742:37–42CrossRefGoogle Scholar
  7. 7.
    Hernández-Plata E, Quiroz-Compeán F, Ramírez-Garcia G, Barrientos EY, Rodríguez-Moralesa NM, Flores A, Wrobel K, Wrobel K, Méndez I, Díaz-Muñoz M, Robles J, Martínez-Alfaro M (2015) Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment. Toxicol Lett 233:78–83CrossRefGoogle Scholar
  8. 8.
    Radogna F, Diederich M, Ghibelli L (2010) Biochem Pharmacol 80:1844–1852CrossRefGoogle Scholar
  9. 9.
    Galano A, Tan DX, Relter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16CrossRefGoogle Scholar
  10. 10.
    Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea MA (2003) J Pineal Res 34:1–10CrossRefGoogle Scholar
  11. 11.
    Velkov ZA, Velkov Y, Galunska BT, Paskalev DN, Tadjer AV (2009) Eur J Med Chem 44:2834–2839CrossRefGoogle Scholar
  12. 12.
    Galano A, Medina ME, Tan DX, Reiter RJ (2015) Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: a physicochemical analysis. J Pineal Res 58:107–116CrossRefGoogle Scholar
  13. 13.
    Limson J, Nyokong T, Daya S (1998) The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study. J Pineal Res 24:15–21CrossRefGoogle Scholar
  14. 14.
    Inorganic and Organic Lead Compounds/IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004). IARC monographs on the evaluation of carcinogenic risks to humans, vol 87, p 378. International Agency for Research on Cancer, Lyon, FranceGoogle Scholar
  15. 15.
    Pan TL, Wang PW, Al-Suwayeh SA, Chen CC, Fang JY (2010) Skin toxicology of lead species evaluated by their permeability and proteomic profiles: a comparison of organic and inorganic lead. Toxicol Lett 197:19–28CrossRefGoogle Scholar
  16. 16.
    Anttila A et al (2006) Monographs on the evaluation of carcinogenic risks to humans, vol 87. In: Inorganic and organic lead compounds. International Agency for Research on Cancer, Lyon, FranceGoogle Scholar
  17. 17.
    Swart M (2003) AddRemove: a new link model for use in QM/MM studies. Int J Quantum Chem 91:177–183CrossRefGoogle Scholar
  18. 18.
    Baerends EJ, Ziegler T, Autschbach J, Bashford D, Bérces A, Bickelhaupt FM, Bo C, Boerrigter PM, Cavallo L, Chong DP, Deng L, Dickson RM, Ellis DE, van Faassen M, Fan L, Fischer TH, Fonseca C, Guerra M, Franchini A, Ghysels A, Giammona SJA, van Gisbergen AW, Götz JA, Groeneveld OV, Gritsenko M, Grüning S, Gusarov FE, Harris P, van den Hoek CR, Jacob H, Jacobsen L, Jensen JW, Kaminski G, van Kessel F, Kootstra A, Kovalenko MV, Krykunov E, van Lenthe DA, McCormack A, Michalak M, Mitoraj SM, Morton J, Neugebauer VP, Nicu L, Noodleman VP, Osinga S, Patchkovskii M, Pavanello PHT, Philipsen D, Post CC, Pye W, Ravenek JI, Rodríguez P, Ros PRT, Schipper H, van Schoot G, Schreckenbach JS, Seldenthuis M, Seth JG, Snijders M, Solà M, Swart D, Swerhone G, te Velde P, Vernooijs L, Versluis L, Visscher O, Visser F, Wang TA, Wesolowski EM, van Wezenbeek G, Wiesenekker SK, Wolff TK, Woo AL Yakovlev (2014) ADF SCM, Theoretical Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
  19. 19.
    Perdew JP, Burke K, Ernzerhof M (1996) Generalized gradient approximation made simple. Phys Rev Lett 77:3865–3868CrossRefGoogle Scholar
  20. 20.
    Snijders JG, Baerends EJ, Vernooijs P (1982) At Data Nucl Data Tables 26:483–509CrossRefGoogle Scholar
  21. 21.
    Bérces A, Dickson RM, Fan L, Jacobsen H, Swerhone D, Ziegler T (1997) Comput Phys Commun 100:247–262CrossRefGoogle Scholar
  22. 22.
    Wolff SK (2005) Int J Quantum Chem 104:645–659CrossRefGoogle Scholar
  23. 23.
    Klamt A (1993) Perkin Trans 2(2):799–805CrossRefGoogle Scholar
  24. 24.
    Boyer TH (1970) Ann Phys 56:474–503CrossRefGoogle Scholar
  25. 25.
    Ziegler T, Rauk A (1977) Theor Chim Acta 45:1–10CrossRefGoogle Scholar
  26. 26.
    Mitoraj M, Michalak A (2007) J Mol Model 13:347–355CrossRefGoogle Scholar
  27. 27.
    Foster JP, Weinhold F (1980) J Am Chem Soc 102:7211–7218CrossRefGoogle Scholar
  28. 28.
    Reed AE, Weinstock RB, Weinhold F (1985) J Chem Phys 83:735–746CrossRefGoogle Scholar

Copyright information

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Authors and Affiliations

  1. 1.Departamento de Alimentos, Centro Interdisciplinario del Noreste (CINUG)Universidad de GuanajuatoGuanajuatoMexico
  2. 2.Departamento de FarmaciaUniversidad de GuanajuatoGuanajuatoMexico
  3. 3.Departamento de QuímicaUniversidad de GuanajuatoGuanajuatoMexico

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