Overexpression of CYP2D6 attenuates the toxicity of MPP+ in actively dividing and differentiated PC12 cells.
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.
Matoh
Naomi
N
Laboratory of Molecular Clinical Chemistry, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
Tanaka
Seigo
S
Takehashi
Masanori
M
Banasik
Marek
M
Stedeford
Todd
T
Masliah
Eliezer
E
Suzuki
Shigehiko
S
Nishimura
Yoshihiko
Y
Ueda
Kunihiro
K
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016716:PC12 Cells / Q000166:cytology / Q000201:enzymology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D006540:Herbicides; D017382:Reactive Oxygen Species; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019389:Cytochrome P-450 CYP2D6; D015655:1-Methyl-4-phenylpyridinium