Summary
Elucidation of the biochemical steps leading to the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-induced degeneration of the nigro-striatal dopamine (DA) pathway has provided new clues to the pathophysiology of Parkinson’s Disease (PD). In line with the enhancement of MPTP toxicity by diethyldithiocarbamate (DDC), here we demonstrate how other CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. In order to provide direct evidence for this isozyme involvement, CYP 2E1 knockout mice were challenged with MPTP or the combined treatment. Here we show that these transgenic mice have a low sensitivity to MPTP alone, similarly to the wild type SVI, suggesting that it is likely that transgenic mice compensate for the missing enzyme. However, in these CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity; this enhancement is instead regularly present in the SVI control animals. This study indicates that the occurrence of CYP 2E1 in C57/bl mouse brain is relevant for MPTP toxicity, and suggests that this isozyme may have a detoxificant role related to the efflux transporter of the toxin.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Brady JF, Ishizaki H, Fukuto JM, Lin MC, Fadel A, Gapac JM, Yang CS (1991) Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites. Chem Res Toxicol 4: 642–647
Corsini GU, Pintus S, Chiueh CC, Weiss JF, Kopin IJ (1985) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice is enhanced by pretreatment with diethyldithiocarbamate. Eur J Pharmacol 119: 127–128
Corsini GU, Maggio R, Vaglini F (2002) Molecular and cellular events regulating dopamine neuron survival. In: Di Chiara G (ed) Dopamine in the CNS II. Springer, Berlin Heidelberg New York Tokyo, pp 321–386 (Handb Exp Pharmacol 154/II)
Lee SS, Buters JT, Pineau T, Fernandez-Salguero P, Gonzalez FJ (1996) Role of CYP 2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 271: 12063–12067
Nissbrandt H, Bergquist F, Jonason J (2001) Inhibition of cytochrome P450 2E1 induces an increase in extracellular dopamine in rat substantia nigra: a new metabolic pathway? Synapse 40: 294–301
Stott I, Murthy A, Robinson A, Thomas NW, Fry JR (1997) Low-dose diethyldithiocarbamate attenuates the hepatotoxicity of 1,3-dichloro-2-propanol and selectively inhibits CYP 2E1 activity in the rat. Hum Exp Toxicol 16: 262–266
Vaglini F, Pardini C, Viaggi C, Batoli C, Dinucci D, Corsini GU (2004) Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson disease. J Neurochem 91: 285–298
Warner M, Wyss A, Yoshida S, Gustafsson JA (1994) Cytochrome P450 enzymes in brain. Academic Press, New York, pp 51–66 (Meth Neurosci, vol XXII)
Watts PM, Riedl AG, Douek DC, Edwards RJ, Boobis AR, Jenner P, Marsden CD (1998) Colocalization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase. Neuroscience 86: 511–519
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer-Verlag
About this paper
Cite this paper
Viaggi, C., Pardini, C., Vaglini, F., Corsini, G.U. (2006). Cytochrome P450 and Parkinson’s disease: protective role of neuronal CYP 2E1 from MPTP toxicity. In: Riederer, P., Reichmann, H., Youdim, M.B.H., Gerlach, M. (eds) Parkinson’s Disease and Related Disorders. Journal of Neural Transmission. Supplementa, vol 70. Springer, Vienna . https://doi.org/10.1007/978-3-211-45295-0_27
Download citation
DOI: https://doi.org/10.1007/978-3-211-45295-0_27
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-28927-3
Online ISBN: 978-3-211-45295-0
eBook Packages: MedicineMedicine (R0)