Involvement of cytochrome P450 2E1 in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced mouse model of Parkinson's disease

• Published in: Journal of neurochemistry Vol. 91; no. 2; pp. 285 - 298
• Main Authors: Vaglini, Francesca, Pardini, Carla, Viaggi, Cristina, Bartoli, Cristina, Dinucci, Dinuccio, Corsini, Giovanni Umberto
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-10-2004; Blackwell
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - metabolism; 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid - metabolism; Allyl Compounds - pharmacology; Animals; Biological and medical sciences; Blotting, Western; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P-450 CYP2E1 - metabolism; Cytochrome P-450 CYP2E1 Inhibitors; cytochrome P450 2E1; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; diethyldithiocarbamate; Disease Models, Animal; Ditiocarb - pharmacology; Dopamine - metabolism; Drug Synergism; Enzyme Inhibitors - pharmacology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Microdialysis; Neostriatum - drug effects; Neostriatum - metabolism; Neostriatum - pathology; Nervous system (semeiology, syndromes); Nervous system as a whole; neurodegeneration; Neurology; neurotoxicity; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - enzymology; Parkinsonian Disorders - pathology; Reverse Transcriptase Polymerase Chain Reaction; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; Sulfides - pharmacology; Tyrosine 3-Monooxygenase - biosynthesis; Animal model; Nervous system diseases; 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Parkinson's disease; cytochrome P450 2E1; Cytochrome P450; Rodentia; Parkinson disease; neurodegeneration; Cerebral disorder; Toxin; Vertebrata; Neurotoxicity; Mammalia; Mouse; Animal; Central nervous system disease; Neurotoxin; Degenerative disease; Degeneration; Dopaminergic pathway; diethyldithiocarbamate; Nigrostriatal pathway; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02720.x

Elucidation of the biochemical steps leading to the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced degeneration of the nigrostriatal dopamine (DA) pathway has provided new clues to the pathophysiology of Parkinson's disease. In line with the enhancement of MPTP toxicity by diethyldithiocarbamate (DDC), here we demonstrate how other cytochrome P450 (CYP) 2E1 inhibitors, such as diallyl sulphide (DAS) and phenylethylisothiocyanate (PIC), also potentiate the selective DA neurone degeneration in C57/bl mice. In addition, we show that CYP 2E1 is present in the brain and in the basal ganglia of this mouse strain, as measured by RT–PCR, western blot analysis and immunohistochemistry. A kinetic analysis of MPTP and its metabolites, by means of the microdialysis technique in the striatum, indicates that no detoxification metabolic pathway is affected by any of these inhibitors. This does not rule out, however, that an undetected detoxification pathway involving CYP 2E1 is operating. 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, similar to their wild‐type counterparts, suggesting that it is likely that transgenic mice compensate for the missing enzyme. However, DDC pretreatment completely fails to enhance MPTP toxicity in CYP 2E1 knockout mice, whereas this enhancement is regularly present in wild‐type animals. This study indicates that the occurrence of CYP 2E1 in C57/bl mouse brain is relevant to MPTP toxicity, and suggests that this isozyme may have a detoxificant role related to the efflux transporter of the toxin.