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Enhancing glutathione synthesis can decrease zinc-mediated toxicity.

Udo Ingbert Walther1, Sabine Christine Walther, Harald Mückter

  • 1Walther Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians Universität München, Nubbaumstr. 26, 80336, Munich, Germany. udo.walther@lrz.uni-muenchen.de

Biological Trace Element Research
|January 15, 2008
PubMed
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Increasing glutathione synthesis with N-acetyl-L-cysteine (NAC) reduced zinc toxicity in some lung cells. However, this effect varied by cell type and cysteine levels, indicating glutathione

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Zinc toxicity is associated with cellular glutathione levels.
  • Decreased glutathione correlates with increased zinc-mediated cytotoxicity.
  • The potential of enhanced glutathione synthesis to mitigate zinc toxicity is unexplored.

Purpose of the Study:

  • To investigate if increasing glutathione synthesis can reduce zinc-induced cytotoxicity.
  • To examine the role of N-acetyl-L-cysteine (NAC) in modulating zinc tolerance across different cell lines.
  • To determine the influence of cysteine availability on NAC's efficacy in boosting glutathione synthesis and zinc tolerance.

Main Methods:

  • Incubation of five cell lines (hepatoma and lung-derived) with zinc chloride.
  • Treatment with N-acetyl-L-cysteine (NAC) to promote glutathione synthesis.
  • Comparison of NAC's effect on zinc tolerance against its D-enantiomer (NADC) and untreated controls.
  • Manipulation of medium cysteine concentrations to assess glutathione synthesis dependency.

Main Results:

  • NAC increased glutathione content in most hepatic and both alveolar epithelial cell lines.
  • Zinc tolerance increased in alveolar epithelial cells treated with NAC compared to NADC.
  • No significant changes in zinc tolerance were observed in native fibroblast-like and hepatoma cells with NAC.
  • Enhanced zinc tolerance in fibroblast-like cells occurred only after pre-depleting cellular glutathione.
  • NAC's efficacy as a glutathione precursor was limited to low cysteine concentrations (<10 µmol/l).

Conclusions:

  • Enhanced glutathione synthesis can antagonize zinc-mediated toxicity, particularly in alveolar epithelial cells.
  • The importance of glutathione synthesis in modulating zinc tolerance varies across different cell types.
  • Cellular characteristics beyond glutathione synthesis may play a role in zinc resistance in certain cell lines.
  • N-acetyl-L-cysteine (NAC) is an inefficient cysteine repleto for glutathione synthesis at higher cysteine concentrations.