Document Detail

Overexpression of CYP2D6 attenuates the toxicity of MPP+ in actively dividing and differentiated PC12 cells.
MedLine Citation:
PMID:  14686785     Owner:  NLM     Status:  MEDLINE    
Clonal pheochromocytoma cell lines overexpressing cytochrome P450 2D6 (CYP2D6) were established. CYP2D6 was localized in the endoplasmic reticulum, and its enzymatic activity in the microsomal fraction was confirmed by using high performance liquid chromatography analysis with [guanidine-14C]debrisoquine as a substrate. Overexpression of CYP2D6 protected both actively dividing and differentiated cells against the toxic effects of 1-methyl-4-phenylpyridinium ion at the concentration range of 20-40 microM, as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The production of reactive oxygen species in the mitochondria was suppressed. The cytotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was unchanged in both actively dividing and differentiated cells overexpressing CYP2D6 versus mock-transfected controls at concentrations up to 500 microM. These results suggest that the lowered enzyme activity of CYP2D6 in individuals termed "poor metabolizers" may represent a risk factor from exposure to select neurotoxicants.
Naomi Matoh; Seigo Tanaka; Masanori Takehashi; Marek Banasik; Todd Stedeford; Eliezer Masliah; Shigehiko Suzuki; Yoshihiko Nishimura; Kunihiro Ueda
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gene expression     Volume:  11     ISSN:  1052-2166     ISO Abbreviation:  Gene Expr.     Publication Date:  2003  
Date Detail:
Created Date:  2003-12-22     Completed Date:  2004-02-02     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9200651     Medline TA:  Gene Expr     Country:  United States    
Other Details:
Languages:  eng     Pagination:  117-24     Citation Subset:  IM    
Laboratory of Molecular Clinical Chemistry, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
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MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
1-Methyl-4-phenylpyridinium / toxicity*
Cell Differentiation / drug effects
Cell Division / drug effects
Cytochrome P-450 CYP2D6 / genetics*,  metabolism
Gene Expression Regulation, Enzymologic / physiology*
Herbicides / toxicity*
Mitochondria / metabolism
PC12 Cells / cytology,  enzymology
Reactive Oxygen Species / metabolism
Grant Support
Reg. No./Substance:
0/Herbicides; 0/Reactive Oxygen Species; 28289-54-5/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 48134-75-4/1-Methyl-4-phenylpyridinium; EC P-450 CYP2D6

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