Open AccessOverexpression of CYP2D6 Attenuates the Toxicity of MPPÞpl in Actively Dividing and Differentiated PC12 Cells
Author(s) -
Naomi Matoh,
Seigo Tanaka,
Masanori Takehashi,
Marek Banasik,
Todd Stedeford,
Eliezer Masliah,
Shigehiko Suzuki,
Yoshihiko Nishimura,
Kunihiro Ueda
Publication year - 2003
Publication title -
gene expression
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 46
eISSN - 1555-3884
pISSN - 1052-2166
DOI - 10.3727/000000003108749017
Subject(s) - cyp2d6 , debrisoquine , endoplasmic reticulum , chemistry , microsome , cytotoxicity , cytochrome p450 , enzyme , bromide , cell culture , toxicity , reactive oxygen species , biochemistry , microbiology and biotechnology , in vitro , biology , genetics , organic chemistry
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.