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Enhancing Glutathione Synthesis can Decrease Zinc-Mediated Toxicity

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Abstract

Zinc toxicity has been linked to cellular glutathione: A decrease in glutathione is followed by an increase in zinc-mediated toxicity. The question arises whether an increase in glutathione synthesis might decrease zinc-mediated cytotoxicity. We incubated five cell lines (hepatoma and lung-derived) with zinc chloride and 2 mmol/l N-acetyl-l-cysteine (NAC) to support glutathione synthesis. In all but one hepatic cell line, the glutathione content was increased by NAC as compared to the d-enantiomere NADC, whereas NADC did not increase GSH content as compared to not treated controls. In both alveolar epithelial cell lines, an increase in zinc tolerance was observed due to NAC as compared to NADC. In native fibroblast-like and the hepatoma cell lines, no changes in zinc tolerance were found due to NAC. In the fibroblast-like cells, zinc tolerance was increased due to NAC only after cellular glutathione had been previously decreased (by lowered cysteine concentrations in the medium). Enhancing glutathione synthesis can antagonize zinc-mediated toxicity in the alveolar epithelial cell lines, whereas some other characteristics than glutathione synthesis might be more important in other cell types. Furthermore, NAC acted as a GSH precursor only at cysteine medium concentrations of 10 µmol/l or below and therefore might be described as a poor cysteine repletor for glutathione synthesis.

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Abbreviations

ARDS:

acute respiratory distress syndrome

Cys:

L-cysteine

DMEMmF12:

Dulbecco’s modified Eagle medium/Ham’s F12 nutrient mix (1:1)

DTNB:

5,5′-dithio-bis(2-nitrobenzoic acid)

EC50 :

concentration for 50% effectivity

EDTA:

N,N,N′,N′-ethylendiaminetetraacetate

Fcs:

fetal calf serum

GC:

glucocorticoid(s)

GR:

glutathione reductase, GSSG reductase

GSH:

glutathione, reduced form

GSSG:

glutathione, oxidized form

HC:

hydrocortisone

MEM:

minimum essential medium

Met:

l-methionine

NAC:

N-acetyl-l-cysteine

NADC:

N-acetyl-d-cysteine

NADPH:

nicotinamide-adenine dinucleotide phosphate, reduced

oxo-Th:

oxo-thiazolidinedione

PBS:

phosphate-buffered saline

SD:

standard deviation

SDS:

sodium laurylsulfate

References

  1. Bennett DR, Baird CJ, Chan KM, Crookes PF, Bremner CG, Gottlieb MM, Naritoku WY (1997) Zinc toxicity following massive coin ingestion. Am J Foren Med Pathol 18:148–153

    Article  CAS  Google Scholar 

  2. Pasqualatto D, Fernandez MC (2003) N-acetylcysteine in zinc chloride poisoning. Toxicol Lett 144(Suppl 1):257

    Google Scholar 

  3. Zerahn B, Kofoed-Enevoldsen A, Jensen BV, Molvig J, Ebbehoj N, Johansen JS, Kanstrup IL (1999) Pulmonary damage after modest exposure to zinc chloride smoke. Am J Respir Crit Care Med 93:885–890

    CAS  Google Scholar 

  4. Frutos-Vivar F, Nin N, Esteban A (2004) Epidemiology of acute lung injury and acute respiratory distress syndrome. Cur Opin Crit Care 10:1–6

    Article  Google Scholar 

  5. Steinebach OM, Wolterbeek HT (1993) Effects of zinc on rat hepatoma HTC cells and primary cultured rat hepatocytes. Toxicol Appl Pharmacol 118:245–254

    Article  PubMed  CAS  Google Scholar 

  6. Danfour M, Schorah CJ, Evans SW (1999) Changes in sensitivity of a human myeloid cell line (U937) to metal toxicity after glutathione depletion. Immunopharmacol Immunotoxicol 21:277–293

    Article  PubMed  CAS  Google Scholar 

  7. Wilhelm B, Walther UI, Fichtl B (2001) Effects of zinc chloride on glutathione and glutathione synthesis rates in various lung cell lines. Arch Toxicol 75:388–394

    Article  PubMed  CAS  Google Scholar 

  8. Walther UI (2004) Changes in the glutathione system of lung cell lines after treatment with hydrocortisone. Arch Toxicol 78:402–409

    Article  PubMed  CAS  Google Scholar 

  9. Walther UI, Czermak A, Mückter H, Walther SC, Fichtl B (2003) Decreased GSSG reductase activity enhances cellular zinc toxicity in three human lung cell lines. Arch Toxicol 77:131–137

    PubMed  CAS  Google Scholar 

  10. Walther UI, Walther SC, Temrück O (2007) Effect of enlarged glutathione on zinc-mediated toxicity in lung-derived cell lines. Toxicol Vitro 21:380–386

    Article  CAS  Google Scholar 

  11. Martell AE, Smith RM (1974) Critical stability constants. Amino acids. Vol 1. Plenum, New York

    Google Scholar 

  12. Gaubin Y, Vaissade F, Croute F, Beau B, Soleihaveoup JP, Murat JC (2000) Implication of free radicals and glutathione in the mechanism of cadmium-induced expression of stress proteins in the A549 human lung cell-line. Biochim Biophys Acta 1495:4–13

    Article  PubMed  CAS  Google Scholar 

  13. Spagnuolo G, D’anto V, Cosentino C, Schmalz G, Schweikl H, Rengo S (2006) Effect of N-acetyl-L-cysteine on ROS production and cell death caused by HEMA in human primary gingival fibroblasts. Biomat 27:1803–1809

    Article  CAS  Google Scholar 

  14. Wang YM, Peng SQ, Zhou Q, Wang MW, Yan CH, Yang HY, Wang GQ (2006) Depletion of intracellular glutathione mediates butenolide-induced cytotoxicity in HepG2 cells. Toxicol Lett 164:231–238

    Article  PubMed  CAS  Google Scholar 

  15. Frazier JM (1990) Multiple endpoint measurements to evaluate the intrinsic cellular toxicity of chemicals. Vitro Toxicol 3:349–358

    CAS  Google Scholar 

  16. Freshney RI (1987) Disaggregation of the tissue and primary culture, in: Cultures of animal cells. - A manual of basic technique, Chp 9. Liss, New York, pp 107–126

    Google Scholar 

  17. Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27:502–522

    Article  PubMed  CAS  Google Scholar 

  18. Read SM, Northcote DH (1981) Minimization of variation in the response to different proteins of the Coomassie Blue G dye-binding assay for protein. Anal Biochem 116:53–64

    Article  PubMed  CAS  Google Scholar 

  19. Soutourina J, Blanquet S, Plateau P (2001) Role of D-cysteine desulfhydrase in the adaptation of Escherichia coli to D-cysteine. J Biol Chem 276:40864–40872

    Article  PubMed  CAS  Google Scholar 

  20. Vitvitsky V, Mosharov E, Tritt M, Ataullakhanov F, Banerjee R (2003) Redox regulation of homocysteine-dependent glutathione synthesis. Redox Rep 8:57–63

    Article  PubMed  CAS  Google Scholar 

  21. Richert L, Binda D, Alexandre E, Bars R, Martin H, and Lasserre-Bigot D (2006) Glutathione prevents cytochrome P450 3A induction by dexamethasone in primary cultures of rat hepatocytes. Toxicol Vitro (in press). DOI 10.1016/j.tiv.2006.07.010

  22. Arakawa M, Ushimaru N, Osada N, Oda T, Ishige K, Ito Y (2006) N-acetylcysteine selectively protects cerebellar granule cells from 4-hydroxynonenal-induced cell death. Neurosci Res 55:255–263

    Article  PubMed  CAS  Google Scholar 

  23. Neal R, Matthews RH, Lutz P, Ercal N (2003) Antioxidant role of N-acetyl cysteine isomers following high dose irradiation. Free Rad Biol Med 34:689–695

    Article  PubMed  CAS  Google Scholar 

  24. Gachot B, Tauc M, Morat L, Poujeol P (1991) Zinc uptake by proximal cells isolated from rabbit kidney: effects of cysteine and histidine. Europ J Physiol 419:583–587

    Article  CAS  Google Scholar 

  25. Cousins RJ, McMahon RJ (2000) Integrative aspects of zinc transporters. J Nutr 130(Suppl 5):1384S–1387S

    PubMed  CAS  Google Scholar 

  26. Inczédy J, Maróthy J (1975) Metal complexes on N-acetyl-cysteine. Acta Chim Acad Sci Hung 86:1–2

    Google Scholar 

  27. Särnstrand B, Tunek A, Sjödin K, Hallberg A (1995) Effects of N-acetylcysdteine stereoisomers on oxygen-induced lung injury in rats. Chem Biol Interact 94:157–164

    Article  PubMed  Google Scholar 

  28. Corcoran GB, Wong BK (1986) Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-d-cysteine in mice. J Pharmacol Exp Therap 238:54–61

    CAS  Google Scholar 

  29. Asayama K, Hayashibe H, Dobashi K, Uchida N, Kato K (1992) Effect of dexamethasone on antioxidant enzymes in fetal rat lungs and kidneys. Biol Neonate 62:136–144

    Article  PubMed  CAS  Google Scholar 

  30. Orzechowski A, Jank M, Gajkowska B, Sadkowski T, Godlewski MM, Ostaszewski P (2003) Delineation of signaling pathway leading to antioxidant-dependent inhibition of dexamethasone-mediated muscle cell death. J Muscle Res Cell Motil 24:33–53

    Article  PubMed  CAS  Google Scholar 

  31. Saether O, Krane J, Risa O, Cejkova J, Midelfart A (2005) High-resolution MAS 1H NMR spectroscopic analysis of rabbit cornea after treatment with dexamethasone and exposure to UV-B radiation. Curr Eye Res 30:1041–1049

    Article  PubMed  CAS  Google Scholar 

  32. Jafari B, Ouyang B, Li LF, Hales CA, Quinn DA (2004) Intracellular glutathione in strech-induced cytokine release from alveolar type-2 like cells. Respirology 9:43–53

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Walther Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians Universität München, Nußbaumstr. 26, 80336, Munich, Germany

    Udo Ingbert Walther, Sabine Christine Walther, Harald Mückter & Burckhard Fichtl

Authors
  1. Udo Ingbert Walther
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  2. Sabine Christine Walther
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  3. Harald Mückter
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  4. Burckhard Fichtl
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Correspondence to Udo Ingbert Walther.

Additional information

This work is dedicated to Peter Eyer on the occasion of his 65th birthday.

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Walther, U.I., Walther, S.C., Mückter, H. et al. Enhancing Glutathione Synthesis can Decrease Zinc-Mediated Toxicity. Biol Trace Elem Res 122, 216–228 (2008). https://doi.org/10.1007/s12011-007-8072-9

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  • DOI: https://doi.org/10.1007/s12011-007-8072-9

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