Dichloroacetic acid up-regulates hepatic glutathione synthesis via the induction of glutamate-cysteine ligase

Biochem Pharmacol. 2012 Feb 1;83(3):427-33. doi: 10.1016/j.bcp.2011.11.012. Epub 2011 Nov 23.

Abstract

Dichloroacetic acid (DCA) has potential for use in cancer therapy and the treatment of metabolic acidosis. However, DCA can create a deficiency of glutathione transferase Zeta (GSTZ1-1). Gstz1 knockout mice have elevated oxidative stress and low glutathione levels that increases their sensitivity to acetaminophen toxicity. As it is highly likely that patients that are treated with DCA will develop drug induced GSTZ1-1 deficiency we considered they could be at risk of elevated toxicity if they are exposed to other drugs that cause oxidative stress or consume glutathione (GSH). To test this hypothesis we treated mice with DCA and acetaminophen (APAP). Surprisingly, the mice pre-treated with DCA suffered less APAP-mediated hepatotoxicity than untreated mice. This protection is most likely due to an increased capacity for the liver to synthesize GSH, since DCA increased the expression and activity of glutamate-cysteine ligase GCL, the rate-limiting enzyme of GSH synthesis. Other pathways for acetaminophen disposal were unchanged or diminished by DCA. Pre-treatment with DCA may be of use in other settings where the maintenance of protective levels of GSH are required. However, DCA may lower the efficacy of drugs that rely on oxidative stress and the depletion of GSH to enhance their cytotoxicity or of drugs that are detoxified by GSH conjugation. Consequently, as the use of DCA in the clinic is likely to increase, it will be critical to evaluate the interactions of DCA with other drugs to ensure the combinations retain their efficacy and do not cause enhanced toxicity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dichloroacetic Acid / pharmacology*
  • Enzyme Induction / drug effects
  • Enzyme Induction / genetics
  • Glutamate-Cysteine Ligase / biosynthesis*
  • Glutamate-Cysteine Ligase / deficiency
  • Glutamate-Cysteine Ligase / genetics
  • Glutathione / biosynthesis*
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Up-Regulation / genetics
  • Up-Regulation / physiology*

Substances

  • Dichloroacetic Acid
  • Glutamate-Cysteine Ligase
  • Glutathione