The effect of diethyldithiocarbamate on the biodisposition of MPTP: an explanation for enhanced neurotoxicity

Eur J Pharmacol. 1987 Sep 11;141(2):209-17. doi: 10.1016/0014-2999(87)90265-2.

Abstract

Diethyldithiocarbamate (DDC) has been reported to exacerbate the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. In this study, the effects of DDC on the biotransformation and distribution of MPTP and 1-methyl-4-phenylpyridinium ion (MPP+, the putative toxic metabolite of MPTP) were investigated. When DDC was administered prior to a standardized dosage of MPTP, the initial concentrations of MPTP in striatum, ventral mesencephalon and frontal cortex were markedly increased when compared to animals given MPTP alone. The pre-administration of DDC also produced increased concentrations of MPP+ in these regions at all time points studied. Further, the rate of disappearance of MPP+ from brain was significantly less in DDC pretreated animals, when compared to animals given MPTP alone. In vitro studies, using either brain homogenates or partially purified MAO-B, showed that DDC enhanced the biotransformation of MPTP. These results suggest that DDC enhances MPTP-induced neurotoxicity by increasing brain concentrations of MPP+. Factors contributing to this increase appear to include greater delivery of MPTP to the central nervous system (CNS), increased biotransformation of MPTP to MPP+ via MAO, and possibly reduced clearance of MPP+ from the brain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Biotransformation / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Ditiocarb / toxicity*
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monoamine Oxidase / metabolism
  • Pyridines / pharmacokinetics*
  • Pyridines / toxicity
  • Tissue Distribution

Substances

  • Pyridines
  • Ditiocarb
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Monoamine Oxidase