Metabolism of 5-(glutathion-S-yl)-alpha-methyldopamine following intracerebroventricular administration to male Sprague-Dawley rats

Chem Res Toxicol. Jul-Aug 1995;8(5):634-41. doi: 10.1021/tx00047a002.

Abstract

5-(Glutathion-S-yl)-alpha-methyldopamine [5-(GSyl)-alpha-MeDA] is a putative metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine and 3,4-(+/-)-(methylenedioxy)methamphetamine. Glutathione (GSH) conjugates of several polyphenols are biologically (re)active. Therefore, as part of our studies on the role of 5-(GSyl)-alpha-MeDA in MDA-mediated neurotoxicity, we determined the regional brain metabolism of 5-(GSyl)-alpha-MeDA (720 nmol) following intracerebroventricular administration to male Sprague-Dawley rats. 5-(GSyl)-alpha-MeDA was rapidly cleared from all brain regions examined, and regional differences in the distribution of gamma-glutamyl transpeptidase (gamma-GT) correlated with the formation of 5-(cystein-S-yl)-alpha-methyldopamine (5-[CYS]-alpha-MeDA). We also observed the formation of 5-(N-acetyl-L-cystein-S-yl)-alpha-MeDA (5-[NAC]-alpha-MeDA) in all brain regions, indicating that the brain has the ability to synthesize mercapturic acids. Peak concentrations of 5-(NAC)-alpha-MeDA were found in the order: hypothalamus > midbrain/diencephalon/telencephalon > pons/medulla > hippocampus > cortex > striatum. In contrast to 5-(GSyl)-alpha-MeDA and 5-(CYS)-alpha-MeDA, 5-(NAC)-alpha-MeDA was eliminated relatively slowly from the brain. Differences were also found in cystein conjugate N-acetyltransferase activity in microsomes prepared from the various brain regions, but little difference was observed in brain cytosolic N-acetyl-L-cysteine conjugate N-deacetylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Chromatography, High Pressure Liquid
  • Deoxyepinephrine / analogs & derivatives*
  • Deoxyepinephrine / metabolism
  • Deoxyepinephrine / pharmacokinetics
  • Deoxyepinephrine / toxicity
  • Glutathione / analogs & derivatives*
  • Glutathione / metabolism
  • Glutathione / pharmacokinetics
  • Glutathione / toxicity
  • Injections, Intraventricular
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • gamma-Glutamyltransferase / metabolism

Substances

  • 5-(glutathion-S-yl)methyldopamine
  • gamma-Glutamyltransferase
  • Glutathione
  • Deoxyepinephrine