Document Detail


Cytochrome P450 2D6 enzyme neuroprotects against 1-methyl-4-phenylpyridinium toxicity in SH-SY5Y neuronal cells.
MedLine Citation:
PMID:  20345925     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cytochrome P450 (CYP) 2D6 is an enzyme that is expressed in liver and brain. It can inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroisoquinoline and beta-carbolines. Genetically slow CYP2D6 metabolizers are at higher risk for developing Parkinson's disease, a risk that increases with exposure to pesticides. The goal of this study was to investigate the neuroprotective role of CYP2D6 in an in-vitro neurotoxicity model. SH-SY5Y human neuroblastoma cells express CYP2D6 as determined by western blotting, immunocytochemistry and enzymatic activity. CYP2D6 metabolized 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin and the CYP2D6-specific inhibitor quinidine (1 microM) blocked 96 +/- 1% of this metabolism, indicating that CYP2D6 is functional in this cell line. Treatment of cells with CYP2D6 inhibitors (quinidine, propanolol, metoprolol or timolol) at varying concentrations significantly increased the neurotoxicity caused by 1-methyl-4-phenylpyridinium (MPP+) at 10 and 25 microM by between 9 +/- 1 and 22 +/- 5% (P < 0.01). We found that CYP3A is also expressed in SH-SY5Y cells and inhibiting CYP3A with ketoconazole significantly increased the cell death caused by 10 and 25 microM of MPP+ by between 8 +/- 1 and 30 +/- 3% (P < 0.001). Inhibiting both CYP2D6 and CYP3A showed an additive effect on MPP+ neurotoxicity. These data further support a possible role for CYP2D6 in neuroprotection from Parkinson's disease-causing neurotoxins, especially in the human brain where expression of CYP2D6 is high in some regions (e.g. substantia nigra).
Authors:
Amandeep Mann; Rachel F Tyndale
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-22
Journal Detail:
Title:  The European journal of neuroscience     Volume:  31     ISSN:  1460-9568     ISO Abbreviation:  Eur. J. Neurosci.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-09     Completed Date:  2010-07-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8918110     Medline TA:  Eur J Neurosci     Country:  France    
Other Details:
Languages:  eng     Pagination:  1185-93     Citation Subset:  IM    
Affiliation:
The Centre for Mental Health and Addictions, and Centre for Addiction and Mental Health Room 4326, University of Toronto, 1 Kings College Circle, Toronto, ON, Canada, M5S 1A8.
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
Acetamides / pharmacology
Cell Line, Tumor
Coumarins / pharmacology
Cytochrome P-450 CYP2D6 / antagonists & inhibitors,  genetics,  metabolism*
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors / pharmacology
Humans
Neuroblastoma / pathology
Neurons / drug effects*,  enzymology
Neurotoxins / pharmacology*
Pyridazines / pharmacology
Quaternary Ammonium Compounds / pharmacology
Grant Support
ID/Acronym/Agency:
14173//Canadian Institutes of Health Research; MOP97751//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/3-(2-(N,N-diethyl-N-methylammonium)ethyl)-7-methoxy-4-methylcoumarin; 0/3-acetamidomethyl-6-methoxycinnolinone; 0/Acetamides; 0/Coumarins; 0/Enzyme Inhibitors; 0/Neurotoxins; 0/Pyridazines; 0/Quaternary Ammonium Compounds; 28289-54-5/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; EC 1.14.14.1/Cytochrome P-450 CYP2D6

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