Glutathione conjugates with dopamine-derived quinones to form reactive or non-reactive glutathione-conjugates

Neurochem Res. 2010 Nov;35(11):1805-18. doi: 10.1007/s11064-010-0247-7. Epub 2010 Aug 19.

Abstract

In this study we demonstrate for the first time that short-lived intermediate glutathione (GSH) conjugates (5-S-GSH-DA-o-quinone and 2-S-GSH-DA-o-quinone) must have first formed when GSH reacted with dopamine (DA)-derived DA-o-quinones without enzymatic catalysis in solutions. These intermediate GSH-conjugates are unstable and would finally transform into reactive or non-reactive GSH-conjugates dependent on ambient reductive forces. We demonstrated that, under sufficient reductive force, the intermediate GSH-conjugates could be reduced and transform into non-reactive 5-S-GSH-DA and 2-S-GSH-DA. However, under insufficient reductive forces, the intermediate GSH-conjugates could cyclize spontaneously to form reactive 7-S-GSH-aminochrome (7-S-GSH-AM). The 7-S-GSH-AM is so reactive and toxic that it could further conjugate with another GSH to form non-reactive 4,7-bi-GSH-5,6-dihydroindole in solutions. Furthermore 7-S-GSH-AM could abrogate tyrosinase activity rapidly and even inhibit proteasome activity in solutions. However, 7-S-GSH-AM could undergo automatically internal rearrangement and transform into non-reactive 7-S-GSH-5,6-dihydroindole if it had not conjugated with GSH. Therefore, insufficient ambient reductive force, such as decreased GSH concentration, could lead to decreased GSH detoxification efficiency for toxic DA quinones. Based on findings in this study, we propose two potential detrimental positive feedback loops involving accelerated DA oxidation, increased GSH consumption and impaired GSH detoxification efficiency, as the potential underlying chemical explanation for dopaminergic neuron degeneration in Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dopamine / analogs & derivatives*
  • Dopamine / chemistry
  • Feedback
  • Glutathione / analogs & derivatives*
  • Glutathione / chemical synthesis
  • Glutathione / chemistry*
  • Glutathione / metabolism
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Monophenol Monooxygenase / antagonists & inhibitors
  • Monophenol Monooxygenase / metabolism
  • Oxidation-Reduction

Substances

  • 7-S-glutathione-aminochrome
  • Indoles
  • dopamine quinone
  • Monophenol Monooxygenase
  • Glutathione
  • Dopamine