Abstract
Neurodegenerative disorders have been linked to the decrease of copper concentrations in different regions of the brain. Therefore, intake of micronutrient supplements could be a therapeutic alternative. Since the copper distribution profile has not been elucidated yet, the aim of this study was to characterize and to analyze the concentration profile of a single administration of copper gluconate to rats by two routes of administration. Male Wistar rats were divided into three groups. The control group received vehicle (n = 5), and the experimental groups received 79.5 mg/kg of copper orally (n = 4–6) or 0.64 mg/kg of copper intravenously. (n = 3–4). Blood, striatum, midbrain and liver samples were collected at different times. Copper concentrations were assessed using atomic absorption spectrophotometry. Copper concentration in samples from the control group were considered as baseline. The highest copper concentration in plasma was observed at 1.5 h after oral administration, while copper was quickly compartmentalized within the first hour after intravenous administration. The striatum evidenced a maximum metal concentration at 0.25 h for both routes of administration, however, the midbrain did not show any change. The highest concentration of the metal was held by the liver. The use of copper salts as replacement therapy should consider its rapid and discrete accumulation into the brain and the rapid and massive distribution of the metal into the liver for both oral and intravenous routes. Development of controlled-release pharmaceutical formulations may overcome the problems that the liver accumulation may imply, particularly, for hepatic copper toxicity.
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Abbreviations
- ANOVA:
-
Analysis of variance
- ALT:
-
Alanine aminotransferase
- ATP7A:
-
ATPase copper-transporting alpha
- ATP7B:
-
ATPase copper-transporting beta
- CaGlu:
-
Calcium gluconate
- Cmax :
-
Concentration maximum
- Ctr1:
-
Copper transporter 1
- Cu:
-
Copper
- CuCl2 :
-
Copper(II) chloride
- CuGlu:
-
Copper gluconate
- CuSO4 :
-
Copper(II) sulphate
- DMT1:
-
Divalent metal transporter 1
- GGT:
-
Gamma-glutamyl transpeptidase
- i.v.:
-
Intravenous
- i.p.:
-
Intraperitoneally
- Kd:
-
Distribution constant
- MT:
-
Metallothionein
- PD:
-
Parkinson’s disease
- p.o.:
-
Per os
- RSD:
-
Relative standard deviation
- SEM:
-
Standard error means
- SN:
-
Substantia nigra
- t1/2 :
-
Half-life
- Tmax :
-
Time required to reach the maximum concentration
- Vd:
-
Volume of distribution
References
Aburto EM, Cribb AE, Fuentealba IC, Ikede BO, Kibenge FSB, Markham F (2001) Morphological and biochemical assessment of the liver response to excess dietary copper in Fischer 344 rats. Can J Vet Res 65:97–103
Ahtoniemi T, Goldsteins G, Keksa-Goldsteine V, Malm T, Kanninen K, Salminen A, Koistinaho J (2007) Pyrrolidine dithiocarbamate inhibits induction of immunoproteasome and decreases survival in a rat model of amyotrophic lateral sclerosis. Mol Pharmacol 71:30–37. https://doi.org/10.1124/mol.106.028415
Alcaraz-Zubeldia M, Rojas P, Boll C, Rios C (2001) Neuroprotective effect of acute and chronic administration of copper “II” sulfate against MPP+neurotoxicity in mice. Neurochem Res 26:59–64. https://doi.org/10.1023/A:1007680616056
Arnal N, Dominici L, Tacconi MJT (2014) Copper-induced alterations in rat brain depends on route of overload and basal copper levels. Nutrition 30:96–106. https://doi.org/10.1016/j.nut.2013.06.009
Choi B, Zheng W (2008) Copper transport to the brain by the blood–brain barrier and blood–CSF barrier. Brain Res. https://doi.org/10.1016/j.brainres.2008.10.056
Collins J (2017) Copper: basic physiological and nutritional aspects. In: Collins J (ed) Molecular, genetic, and nutritional aspects of major and trace minerals. Elsevier, Amsterdam, pp 60–83
Comission for analytical control and expansion of coverage (2014) Criteria for internal validation and confirmation of physicochemical methods. National Advisory Committe for Standardization of Regulation and Health Promotion
National Advisory Committe for Standardization of Regulation and Health Promotion (2013) Official Mexican Standard NOM-177-SSA1-2013
Coudray C, Rambeau M, Feillet-Coudray C, Gueux E, Tressol JC, Mazur A, Rayssiguier Y (2005) Study of magnesium bioavailability from ten organic and inorganic Mg salts in Mg-depleted rats using a stable isotope approach. Magn Res 18:215–223
Creech BL, Spears JW, Flowers WL, Hill GM, Lloyd KE, Armstrong TA, Engle TE (2004) Effect of dietary trace mineral concentration and source (inorganic vs. chelated) on performance, mineral status, and fecal mineral excretion in pigs from weaning through finishing. J Anim Sci 82:2140–2147. https://doi.org/10.2527/2004.8272140x
Dameron CT, Howe P, WHO Task Group on Environmental Health Criteria for Copper, United Nations Environment Programme, International Labour Organisation, World Health Organization, Inter-Organization Programme for the Sound Management of Chemicals, International Program on Chemical Safety (1998) Copper. World Health Organization, Geneva
Davies KM, Bohic S, Carmona A, Ortega R, Cottam V, Hare DJ, Finberg JPM, Reyes S, Halliday GM, Mercer JFB, Double KL (2014) Copper pathology in vulnerable brain regions in Parkinson’s disease. Neurobiol Aging 35:858–866. https://doi.org/10.1016/j.neurobiolaging.2013.09.034
De Souza AR, Martins LP, De Faria LC, Martins MEP, Fereira RN, Da Silva AML, Gil ES, Da Conceição EC (2007) Studies on the bioavailability of zinc in rats supplementated with two different zinc-methionine compounds. Lat Am J Pharm 26:825–830
Dijkstra M, Kuipers F, Van Den Berg GJ, Havinga R, Vonk RJ (1997) Differences in hepatic processing of dietary and intravenously administered copper in rats. Hepatology 26:962–966. https://doi.org/10.1002/hep.510260424
Du Z, Hemken RW, Jackson JA, Trammell DS (1996) Utilization of copper in copper proteinate, copper lysine, and cupric sulfate using the rat as an experimental model. J Anim Sci 74:1657–1663. https://doi.org/10.2527/1996.7471657x
Dunn MA, Green MH, Leach RM (1991) Kinetics of copper metabolism in rats: a compartmental model. Am J Physiol 261:E115–E125. https://doi.org/10.1152/ajpendo.1991.261.1.E115
Ellingsen DG, Møller LB, Aaseth J (2015) Copper. In: Nordberg GF, Fowler BA, Nordberg M (eds) Handbook on the toxicology of metals. Elsevier, Amsterdam, pp 765–786
Famitafreshi H, Karimian M (2019) Modulation of catalase, copper and zinc in the hippocampus and the prefrontal cortex in social isolation-induced depression in male rats. Acta Neurobiol Exp (Wars) 79:184–192
Feillet-Coudray C, Coudray C, Bayle D, Rock E, Rayssiguier Y, Mazur A (2000) Response of diamine oxidase and other plasma copper biomarkers to various dietary copper intakes in the rat and evaluation of copper absorption with a stable isotope. Br J Nutr 83:561–568. https://doi.org/10.1017/s0007114500000702
Gaetke LM, Chow-Johnson HS, Chow CK (2014) Copper: toxicological relevance and mechanisms. Arch Toxicol 88:1929–1938. https://doi.org/10.1007/s00204-014-1355-y
Gaggelli E, Kozlowski H, Valensin D, Valensin G (2006) Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyotrophic lateral sclerosis). Chem Rev 106(6):1995–2044
Genoud S, Senior AM, Hare DJ, Double KL (2020) Meta-analysis of copper and iron in Parkinson’s disease brain and biofluids. Mov Disord 35:662–671. https://doi.org/10.1002/mds.27947
Glossmann H, Neville DMJ (1972) r-Glutamyltransferase in kidney brush border membranes. FEBS Lett 19:340–344
Helsel ME, Franz KJ (2015) Pharmacological activity of metal binding agents that alter copper bioavailability. Dalt Trans 44:8760–8770. https://doi.org/10.1039/c5dt00634a
Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim SC, Leong SL, Wilkins S, George J, Roberts BR, Pham CLL, Liu X, Chiu FCK, Shackleford DM, Powell AK, Masters CL, Bush AI, O’Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ (2012) The hypoxia imaging agent Cu II(ATSM) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease. J Exp Med 209:837–854. https://doi.org/10.1084/jem.20112285
Irato P, Sturniolo GC, Giacon G, Magro A, D’Inca R, Mestriner C, Albergoni V (1996) Effect of zinc supplementation on metallothionein, copper, and zinc concentration in various tissues of copper-loaded rats. Biol Trace Elem Res 51:87–96. https://doi.org/10.1007/BF02790151
Kuo YM, Zhou B, Cosco D, Gitschier J (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA 98:6836–6841. https://doi.org/10.1073/pnas.111057298
Kuo Y-M, Gybina AA, Pyatskowit JW, Gitschier J, Prohaska JR (2006) Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J Nutr 136:21–26. https://doi.org/10.1093/jn/136.1.21
Lee I-C, Ko J-W, Park S-H, Lim J-O, Shin I-S, Moon C, Kim S-H, Heo J-D, Kim J-C (2016a) Comparative toxicity and biodistribution of copper nanoparticles and cupric ions in rats. Int J Nanomedicine 11:2883–2900. https://doi.org/10.2147/IJN.S106346
Lee I-C, Ko J-W, Park S-H, Shin N-R, Shin I-S, Moon C, Kim J-H, Kim H-C, Kim J-C (2016b) Comparative toxicity and biodistribution assessments in rats following subchronic oral exposure to copper nanoparticles and microparticles. Part Fibre Toxicol 13:2–16. https://doi.org/10.1186/s12989-016-0169-x
Liu B, Xiong P, Chen N, He J, Lin G, Xue Y, Li W, Yu D (2016) Effects of replacing of inorganic trace minerals by organically bound trace minerals on growth performance, tissue mineral status, and fecal mineral excretion in commercial grower-finisher pigs. Biol Trace Elem Res 173:316–324. https://doi.org/10.1007/s12011-016-0658-7
Manrique-Arias JC, Carrasco-Hernández J, Reyes PG, Ávila-Rodríguez MA (2016) Biodistribution in rats and estimates of doses to humans from 64CuCl2, a potential theranostic tracer. Appl Radiat Isot 115:18–22. https://doi.org/10.1016/j.apradiso.2016.05.030
Meeuwsen JC, Sirois JJ, Samuel Bradford C, Labut EM, Lopez NI, Hurst JK, Beckman JS (2016) Complex role of copper delivery by CuATSM to superoxide dismutase (SOD1) in mouse models of ALS. Free Radic Biol Med 100:S105. https://doi.org/10.1016/j.freeradbiomed.2016.10.268
Nederbragt H, Lagerwerf AJ (1986) Strain-related patterns of biliary excretion and hepatic distribution of copper in the rat. Hepatology 6:601–607. https://doi.org/10.1002/hep.1840060409
Secretariat of Agriculture, Livestock Rural Development, Fisheries and Food (1999). NOM-062-ZOO-1999 ESPECIFICACIONES TECNICAS PARA LA PRODUCCION, CUIDADO Y USO DE LOS ANIMALES DE LABORATORIO.
Nose Y, Wood LK, Kim B-E, Prohaska JR, Fry RS, Spears JW, Thiele DJ (2010) Ctr1 is an apical copper transporter in mammalian intestinal epithelial cells in vivo that is controlled at the level of protein stability. J Biol Chem 285:32385–32392. https://doi.org/10.1074/jbc.M110.143826
Owen CA (1964) Absorption and excretion of Cu 64-labeled copper by the rat. Am J Physiol Content 207:1203–1206. https://doi.org/10.1152/ajplegacy.1964.207.6.1203
Owen CA, Hazelrig J (1968) Copper deficiency and copper toxicity in the rat. Am J Physiol Content 215:334–338. https://doi.org/10.1152/ajplegacy.1968.215.2.334
Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S (2008) The current state of serum biomarkers of hepatotoxicity. Toxicology 245:194–205. https://doi.org/10.1016/j.tox.2007.11.021
Pal A, Prasad R (2016) Regional distribution of copper, zinc and iron in brain of Wistar rat model for non-Wilsonian brain copper toxicosis. Indian J Clin Biochem 31:93–98. https://doi.org/10.1007/s12291-015-0503-3
Petris MJ, Smith K, Lee J, Thiele DJ (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem 278:9639–9646. https://doi.org/10.1074/jbc.M209455200
Platonova NA, Barabanova SV, Povalikhin RG, Tsymbalenko NV, Danilovskii MA, Voronina OV, Dorokhova II, Puchkova LV (2005) In Vivo expression of copper-transporting proteins in rat brain regions. Biol Bull 32:108–120. https://doi.org/10.1007/s10525-005-0016-3
Prohaska JR (2011) Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases). Adv Nutr 2:89–95. https://doi.org/10.3945/an.110.000208
Ransom BS, Solioz M, Krewski D, Aggett P, Aw T-C, Baker S, Crump K, Dourson M, Haber L, Hertzberg R, Keen CL, Meek B, Rudenko L, Schoeny R, Slob W, Starr TB (2007) Copper and human health: biochemistry, genetics, and strategies for modeling dose–response relationships. J Toxicol Environ Health 10:157–222. https://doi.org/10.1080/10937400600755911
Reitman S, Frankel S (1957) A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63
Ríos C, Alvarez-Vega R, Rojas P (1995) Depletion of copper and manganese in brain after MPTP treatment of mice. Pharmacol Toxicol 76:348–352. https://doi.org/10.1111/j.1600-0773.1995.tb00160.x
Roberts BR, Lim NKH, McAllum EJ, Donnelly PS, Hare DJ, Doble PA, Turner BJ, Price KA, Lim SC, Paterson BM, Hickey JL, Rhoads TW, Williams JR, Kanninen KM, Hung LW, Liddell JR, Grubman A, Monty JF, Llanos RM, Kramer DR, Mercer JFB, Bush AI, Masters CL, Duce JA, Li QX, Beckman JS, Barnham KJ, White AR, Crouch PJ (2014) Oral treatment with CuII(ATSM) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 34:8021–8031. https://doi.org/10.1523/JNEUROSCI.4196-13.2014
Rojas LX, Mcdowell LR, Cousins RJ, Gmarttn F, Wilkinson NS, Johnson AB, Velasquez JB (1996) Interaction of different organic and inorganic zinc and copper sources fed to rats. J Trace Elem Med Biol 10:139–144. https://doi.org/10.1016/S0946-672X(96)80023-X
Rubio-Osornio M, Montes S, Heras-Romero Y, Guevara J, Rubio C, Aguilera P, Rivera-Mancia S, Floriano-Sánchez E, Monroy-Noyola A, Ríos C (2013) Induction of ferroxidase enzymatic activity by copper reduces MPP+-evoked neurotoxicity in rats. Neurosci Res 75:250–255. https://doi.org/10.1016/j.neures.2012.12.003
Samson SL-A, Gedamu L (1997) Molecular analyses of metallothionein gene regulation. Prog Nucleic Acid Res Mol Biol 59:257–288. https://doi.org/10.1016/S0079-6603(08)61034-X
Sandstead HH (1995) Requirements and toxicity of essential illustrated by zinc and copper1,2. Am J Nutr 61:621S-624S
Schoonover KE, Queern SL, Lapi SE, Roberts RC (2020) Impaired copper transport in schizophrenia results in a copper- deficient brain state: a new side to the dysbindin story. Kirsten World J Bio Pyschiatry 21:13–28. https://doi.org/10.1080/15622975.2018.1523562
Tang H, Xu M, Zhou XR, Zhang Y, Zhao L, Ye G, Shi F, Lv C, Li Y (2018) Acute toxicity and biodistribution of different sized copper nano-particles in rats after oral administration. Mater Sci Eng C 93:649–663. https://doi.org/10.1016/j.msec.2018.08.032
Tokuda E, Furukawa Y (2016) Copper homeostasis as a therapeutic target in amyotrophic lateral sclerosis with SOD1 mutations. Int J Mol Sci 1:11. https://doi.org/10.3390/ijms17050636
ICH Topic Q 2 (R1) Validation of Analytical Procedures: Text and Methodology Step 5 note for guidance on validation of analytical procedures: text and methodology (CPMP/ICH/381/95) approval by CPMP november 1994 date for coming into operation, 1995.
Uauy R, Olivares M, Gonzales M (1998) Essentiality of copper in humans | The American Journal of Clinical Nutrition | Oxford Academic. Am J Clin Nutr 67:952S-959S
Uitti RJ, Rajput AH, Rozdilsky B, Bickis M, Wollin T, Yuen WK (1989) Regional metal concentrations in parkinson’s disease, other chronic neurological diseases, and control brains. J Can des Sci Neurol 16:310–314. https://doi.org/10.1017/S0317167100029140
Waalkes MP, Klaassen CD (1985) Concentration of metallothionein in major organs of rats after administration of various metals. Toxicol Sci 5:473–477. https://doi.org/10.1093/toxsci/5.3.473
Wang G, Liu L, Wang Z, Pei X, Tao W, Xiao Z, Liu B, Wang M, Lin G, Ao T (2019) Comparison of inorganic and organically bound trace minerals on tissue mineral deposition and fecal excretion in broiler breeders. Biol Trace Elem Res 189:224–232. https://doi.org/10.1007/s12011-018-1460-5
Williams JR, Trias E, Beilby PR, Lopez NI, Labut EM, Bradford CS, Roberts BR, McAllum EJ, Crouch PJ, Rhoads TW, Pereira C, Son M, Elliott JL, Franco MC, Estévez AG, Barbeito L, Beckman JS (2016) Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD. Neurobiol Dis 89:1–9. https://doi.org/10.1016/j.nbd.2016.01.020
Yasuno T, Okamoto H, Nagai M, Kimura S, Yamamoto T, Nagano K, Furubayashi T, Yoshikawa Y, Yasui H, Katsumi H, Sakane T, Yamamoto A (2011) The disposition and intestinal absorption of zinc in rats. Eur J Pharm Sci 44:410–415. https://doi.org/10.1016/j.ejps.2011.08.024
Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: AN add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Progr Biomed 99:306–314. https://doi.org/10.1016/j.cmpb.2010.01.007
Acknowledgements
The authors would like to acknowledge the technical assistance provided by IBQ. Dulce Zamora Mondragón and QFB. Sarai Valencia Ruiz. García-Martínez Betzabeth Anali received a fellowship for her doctoral studies (Grant No. 455951) granted by CONACYT (Consejo Nacional de Ciencia y Tecnología) during the development of this study.
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G-MBA: Research, project administration, formal analysis, writing of the original draft; MS: Validation, formal analysis; T-LL: Methodology, formal analysis, writing, review and editing of the manuscript; Q-GD: Formal analysis, supervision, writing, review and editing of the manuscript; MCLM: Research, writing, review and editing of the manuscript; B-FV: Supervision, formal analysis; RC: Conception, resources, writing, review and editing of the manuscript.
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All experimental procedures were approved by the Local Ethics Committee for the Management of Laboratory Animals of the Unit of Production and Experimentation of Laboratory Animals from UAM-X (Protocol No. 170) and the Internal Committee for Care of Laboratory Animals from the National Institute of Neurology and Neurosurgery (Protocol No. 135/16).
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García-Martínez, B.A., Montes, S., Tristán-López, L. et al. Copper biodistribution after acute systemic administration of copper gluconate to rats. Biometals 34, 687–700 (2021). https://doi.org/10.1007/s10534-021-00304-1
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DOI: https://doi.org/10.1007/s10534-021-00304-1