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Essential Metal Status, Prooxidant/Antioxidant Effects of MiADMSA in Male Rats: Age-related Effects

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Abstract

Thiols are known to act as protectants in the biological system for their involvement in a number of metabolic regulations. In this study, we investigated the effect of a new and potent thiol-chelating agent, monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), an analog of meso 2,3-dimercaptosuccinic acid, to find out if it could act as a prooxidant (because of its lipophilic character) or antioxidant (because of thiol moiety) that could supplement its chelating properties in different age groups of male rats (young, adult, and old rats) and produce effective clinical recoveries in the treatment of metal intoxication. Animals were treated with 25, 50, and 100 mg/kg of MiADMSA, i.p, once daily for 1 week to assess the effect on the antioxidant system in major organs based on sensitive biochemical variables indicative of oxidative stress. Results suggested that MiADMSA administration increased the activity of d-aminolevulinic acid dehydratase in all the age groups and increased blood glutathione (GSH) levels in young rats. MiADMSA also potentiated the synthesis of metallothioneine in liver and kidneys and GSH levels in liver and brain. Apart from this it also significantly reduced the glutathione disulfide levels in tissues. However, administration of MiADMSA caused some concern over the copper loss. MiADMSA was found to be safe in rats of all ages.

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References

  1. Shan X, Aw TY, Jones DP (1990) Glutathione-dependent protection against oxidative injury. Pharmacol Ther 47:61–71

    Article  PubMed  CAS  Google Scholar 

  2. Hultberg B, Anderson A, Isaksson A (2001) Interaction of metal and thiols in cell damage and glutathione distribution: potentiation of mercury toxicity by dithiothreitol. Toxicology 156:93–100

    Article  PubMed  CAS  Google Scholar 

  3. Winterbourn CC, Metodiewa D (1999) Reactivity of biologically important thiol compound with superoxide and hydrogen peroxide. Free Radic Biol Med 27:322–328

    Article  PubMed  CAS  Google Scholar 

  4. Ziegler JL, Strull WM, Larsen RC, Martin AR, Coates TJ (1985) Stress and medical training. West J Med 142:814–819

    PubMed  CAS  Google Scholar 

  5. Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L (1997) Redox regulation of NF-kappa β activation. Free Radic Biol Med 22:1115–1126

    Article  PubMed  CAS  Google Scholar 

  6. Knebel A, Rahmsdorf J, Ullrich A, Herrlich P (1996) Dephosphorylation of tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J 15:5314–5325

    PubMed  CAS  Google Scholar 

  7. Sen CK, Packer L (1996) Antioxidant and redox regulation of gene transcription. FASEB J 10:709–720

    PubMed  CAS  Google Scholar 

  8. Ercal N, Treeratphan P, Hammond TC, Matthews RH, Grannemann NH, Spitz DR (1996) In vivo indices of oxidative stress in lead exposed C57BL/6 mice are reduced by the treatment with meso 2, 3-dimercaptosuccinic acid or n-acetyl cysteine. Free Radic Biol Med 22:157–161

    Article  Google Scholar 

  9. Yoon SJ, Koh HY, Floyd RA, Park JW (2000) Copper, zinc superoxide dismutase enhances DNA damage and mutagenicity induced by cysteine/iron. Mutat Res 448:97–104

    PubMed  CAS  Google Scholar 

  10. Glatt H, Sabjic MP, Oesch F (1983) Mutagenicity of glutathione and cysteine in the Ames test. Science 220:961–962

    Article  PubMed  CAS  Google Scholar 

  11. Glatt H, Oesch F (1985) Mutagenicity of cysteine and penicillamine and its enantiomeric selectivity. Biochem Pharmacol 34:3725–3728

    Article  PubMed  CAS  Google Scholar 

  12. Stark AA, Zeiger E, Pagano DA (1988) Glutathione mutagenesis in Salmonella typhemurium is a gamma-glutamyl transpeptidase-enhanced process involving active oxygen species. Carcinogenesis 9:771–777

    Article  PubMed  CAS  Google Scholar 

  13. Stark AA, Arod A, Siskindovich S, Pagano DA, Zeiger E (1989) Effect of pH on mutagenesis by thiols in Salmonella typhemurium TA 102. Mutat Res 224:89–94

    Article  PubMed  CAS  Google Scholar 

  14. Glatt H (1990) Endogenous mutagens derived from amino acids. Mutat Res 238:235–243

    PubMed  CAS  Google Scholar 

  15. Sha SH, Schacht J (2000) Antioxidants attenuate gentamicin-induced free radical formation in vitro and ototoxicity in vivo: D-methionine is a potential protectant. Hear Res 142:34–40

    Article  PubMed  CAS  Google Scholar 

  16. Standtman ER (1983) Oxidation of free amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. Annu Rev Biochem 62:797–821

    Article  Google Scholar 

  17. Blanusa M, Prester L, Piasek M, Kostial K, Jones MM, Singh PK (1997) Monoisoamyl ester of DMSA reduces 203Hg(NO3)2 retention in rats: 1. Chelation therapy during pregnancy. J Trace Elem Exp Med 10:173–181

    Article  CAS  Google Scholar 

  18. Gale GR, Smith AB, Jones MM, Singh PK (1993) Meso-2, 3-dimercaptosuccinic acid monoalkyl esters: effects on mercury levels in mice. Toxicology 81:49–56

    Article  PubMed  CAS  Google Scholar 

  19. Grandjean P, Jacobsen IA, Jorgensen PJ (1991) Chronic lead poisoning treatment with dimercaptosuccinic acid. Pharmacol Toxicol 68:266–269

    PubMed  CAS  Google Scholar 

  20. Graziano JH, Siris ES, LoIacono N, Silverberg SJ, Turgeon L (1985) 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 37:431–438

    Article  PubMed  CAS  Google Scholar 

  21. Pande M, Mehta A, Pant BP, Flora SJS (2001) Combined administration of a chelating agent and an antioxidant in the prevention and treatment of acute lead intoxication in rats. Environ Toxicol Pharmacol 9:173–184

    Article  PubMed  CAS  Google Scholar 

  22. Flora SJS, Bhadauria S, Pant SC, Dhaked RK (2005) Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats. Life Sci 77:2324–2337

    Article  PubMed  CAS  Google Scholar 

  23. Mehta A, Flora SJS (2001) Possible role of metal redistribution, hepatotoxicity and oxidative stress in chelating agents induced hepatic and renal metallothioneine in rats. Food Chem Toxicol 39:1029–1038

    Article  PubMed  CAS  Google Scholar 

  24. Mehta A, Kannan GM, Dube SN, Pant BP, Pant SC, Flora SJS (2002) Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA I. Changes in male rats. J Appl Toxicol 22:359–369

    Article  PubMed  CAS  Google Scholar 

  25. Flora SJS, Mehta A (2003) Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA II. Changes in female rats. J Appl Toxicol 23:97–102

    Article  PubMed  CAS  Google Scholar 

  26. Jones MM, Singh PK, Gale GR, Smith AB, Atkins LM (1992) Cadmium mobilization in vivo by intraperitoneal or oral administration of monoalkyl esters of meso 2,3-dimercaptosuccinic acid. Pharmacol Toxicol 70:336–340

    Article  PubMed  CAS  Google Scholar 

  27. Flora SJS, Kumar P (1996) Biochemical and immunological alterations following repeated gallium arsenide exposure and their recoveries by meso 2,3-dimercaptosuccinic acid and 2,3-dimercaptopropane 1-sulfonate administration in rats. Environ Toxicol Pharmacol 2:315–320

    Article  CAS  Google Scholar 

  28. Flora SJS, Bhattacharya R, Vijayaraghavan R (1995) Combined therapeutic potential of meso 2,3-dimercaptosuccinic acid and calcium disodium edetate in the mobilization and distribution of lead in experimental lead intoxication in rats. Fundam Appl Toxicol 25:233–240

    Article  PubMed  CAS  Google Scholar 

  29. Gong Z, Evans HL (1997) Effect of chelation with meso-dimercaptosuccinic acid (DMSA) before and after the appearance of lead induced neurotoxicity in the rat. Toxicol Appl Pharmacol 144:205–214

    Article  PubMed  CAS  Google Scholar 

  30. Lifshitz M, Hashkanazi R, Phillip M (1997) The effect of 2,3-dimercaptosuccinic acid in the treatment of lead poisoning in adults. Ann Med 29:83–85

    PubMed  CAS  Google Scholar 

  31. Berlin A, Schaller KH (1974) European standardized method for the determination of delta aminolevulinic acid dehydratase activity in blood. Z Klin Chem Klin Biochem 12:389–390

    PubMed  CAS  Google Scholar 

  32. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem 82:70–77

    Article  PubMed  CAS  Google Scholar 

  33. Grandjean P (1979) Occupational lead exposure in Denmark; screening with a haematofluorimeter. Br J Ind Med 36:52–58

    PubMed  CAS  Google Scholar 

  34. Clegg JW, King EJ (1942) Estimation of the hemoglobin by the alkaline haematin method. BMJ ii:329–330

    Google Scholar 

  35. Winterbourn CC, Hawkins RE, Brain M, Carrell RW (1972) The estimation of red cell superoxide activity. J Lab Clin Med 337–341

  36. Nishikimi M, Appaji N, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulphate and molecular oxygen. Biochem Biophys Res Commun 46:849–854

    Article  PubMed  CAS  Google Scholar 

  37. Sinha AK (1972) Calorimetric assay of catalase. Anal Biochem 47:389–394

    Article  PubMed  CAS  Google Scholar 

  38. Wilber KM, Baerheim F, Shapiro DW (1949) The thiobarbituric acid reagent as a test for the oxidation of unsaturated fatty acid by various reagents. Arch Biochem Biophys 24:304–313

    Google Scholar 

  39. Hissin PJ, Hilf R (1973) A fluorimetric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74:214–226

    Article  Google Scholar 

  40. Onosaka S, Cherian MG (1982) Comparison of metallothioneine determination by polarographic and cadmium saturation method. Toxicol Appl Pharmacol 63:270–274

    Article  PubMed  CAS  Google Scholar 

  41. Kagi JH, Schaffer A (1988) Biochemistry of metallothioneine. Biochem 27:8509–8515

    Article  CAS  Google Scholar 

  42. Parker MM, Humoller FL, Mahler DJ (1967) Determination of copper and zinc in biological materials. Clin Chem 13:40–48

    PubMed  CAS  Google Scholar 

  43. Peng J, Jones GL, Watson K (2000) Stress proteins as biomarkers of oxidative stress: effect of antioxidant supplements. Free Radic Biol Med 28:1598–1606

    Article  PubMed  CAS  Google Scholar 

  44. Halliwell B, Gutteridge JMC (1989) Free radical in biology and medicine, 2nd edn. Clarendon, Oxford, UK

    Google Scholar 

  45. Diplock AT, Charleux JL, Crozier-Willi G, Kok FJ, Rice-Evans C, Roberfroid M, Stahl W, Ina-Ribes J (1998) Functional food science and defence against reactive oxygen species. Br J Nutr 80(Suppl):S77–S112

    Article  PubMed  CAS  Google Scholar 

  46. Markant A, Pallauf J (1996) Metallothioneine and zinc as potential antioxidants in radical-induced lipid peroxidation in cultured hepatocytes. J Trace Elem Med Biol 10:88–95

    PubMed  CAS  Google Scholar 

  47. Esterbauer H (1993) Cytotoxicity and genotoxicity of lipid peroxidation products. Am J Clin Nutr 57:789S–800S

    Google Scholar 

  48. Miura T, Muraoka S, Ogiso T (1997) Antioxidant activity of metallothioneine compared with reduced glutathione. Life Sci 60:301–309

    Article  Google Scholar 

  49. Meilhac O, Zhou M, Santanam N, Parthasarthy S (2000) Lipid peroxides induced expression of catalase in cultured vascular cells. J Lipid Res 41:1205–1213

    PubMed  CAS  Google Scholar 

  50. Sato K, Akaike T, Kohno M, Ando M, Maeda H (1992) Hydroxyl radical production by H2O2 plus Cu, Zn-superoxide dismutase reflects the activity of free copper released from oxidatively damage enzyme. J Biol Chem 267:25371–25377

    PubMed  CAS  Google Scholar 

  51. Gianness M, Corso AD, Cappello M, Voltarelli M, Marini I, Barsacchi D, Graland D, Camici M, Mura U (1993) Thiol-dependent metal-catalyzed oxidation o bovine lens aldose reductase: I. Studies on the modification process. Arch Biochem Biophys 300:423–429

    Article  Google Scholar 

  52. Bose S, Mukhopadhyay B, Chaudhury S, Bhattacharya S (1994) Correlation of metal distribution, reduced glutathione and metallothioneine levels in liver and kidney in rat. Ind J Exp Biol 32:679–681

    CAS  Google Scholar 

  53. Huang PC, Lin LY (1989) Metallothioneine as a stress protein. In: Chiou SH, Wang KT, Wu Sh (eds) Biologically active proteins and peptides. Academic Sinica Press, Beijing, China, pp 101–112

    Google Scholar 

  54. Nehru B, Anand P (2005) Oxidative damage following chronic aluminum exposure in adult and pup rat brains. J Trace Elem Med Biol 19:203–208

    PubMed  CAS  Google Scholar 

  55. Fridovick I (1975) Superoxide radicals: an endogenous toxicant. Annu Rev Pharmacol Toxicol 23:239–253

    Article  Google Scholar 

  56. Blanusa M, Piasek M, Kostial K, Momcilovic B, Kosicek M, Jones MM, Singh PK (1993) The influence of monoisoamyl-2, 3-dimercaptosuccinate treatment on essential element content in rats. In: 8th international symposium on trace elements in man and animals (TEMA-8), Dresden, Germany, abstracts, p 159

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Acknowledgments

The authors thank Dr. R. Vijayaraghavan, Director, DRDE, for his constant support and encouragement. One of the authors (AM) also thanks the Ministry of Defence for a research fellowship.

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  1. Department of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, India

    S. J. S. Flora, Ashish Mehta, Pratibha Gautam & P. C. Jatav

  2. Division of Synthetic Chemistry, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, India

    Uma Pathak

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  1. S. J. S. Flora
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Correspondence to S. J. S. Flora.

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Flora, S.J.S., Mehta, A., Gautam, P. et al. Essential Metal Status, Prooxidant/Antioxidant Effects of MiADMSA in Male Rats: Age-related Effects. Biol Trace Elem Res 120, 235–247 (2007). https://doi.org/10.1007/s12011-007-0064-2

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