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Role of CYP2E1 in the mouse model of MPTP toxicity

Carla Pardini1, Francesca Vaglini, Cristina Viaggi

  • 1Department of Neuroscience, Section of Pharmacology, University of Pisa, Via Roma 55, Pisa, Italy.

Parkinsonism & Related Disorders
|June 28, 2008
PubMed

Insights

Diethyldithiocarbamate (DDC) increases 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity by affecting CYP2E1. CYP2E1-null mice showed reduced sensitivity, suggesting a role for CYP2E1 in MPP(+) accumulation and efflux.

Area of Science:

  • Neuroscience
  • Toxicology
  • Pharmacology

Background:

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that selectively damages dopaminergic neurons.
  • Diethyldithiocarbamate (DDC) is known to potentiate MPTP toxicity in mice.

Purpose of the Study:

  • To investigate the role of Cytochrome P450 2E1 (CYP2E1) in MPTP-induced neurotoxicity.
  • To elucidate the mechanism by which DDC enhances MPTP toxicity.

Main Methods:

  • MPTP toxicity assays in C57Bl mice and CYP2E1-null mice.
  • Measurement of 1-methyl-4-phenylpyridinium ion (MPP(+)) levels in the striatum.
  • In vitro studies using mesencephalic cell cultures from CYP2E1-null mice.

Main Results:

  • DDC potentiated MPTP toxicity and striatal MPP(+) accumulation in C57Bl mice, linked to brain CYP2E1 inhibition.
  • CYP2E1-null mice exhibited no enhanced sensitivity to MPTP or MPP(+) accumulation.
  • Dopaminergic neurons from CYP2E1-null mice showed reduced sensitivity to MPP(+) intoxication, with increased intracellular toxin accumulation.

Conclusions:

  • CYP2E1 plays a critical role in MPTP-induced neurotoxicity and striatal MPP(+) accumulation.
  • CYP2E1-null mice compensate for the lack of CYP2E1, potentially via other isozymes.
  • CYP2E1 appears to be involved in the storage and efflux of MPP(+), influencing its neurotoxic effects.

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