title: Endogenous dopamine is involved in the herbicide paraquat-induced dopaminergic cell death.
abstract: The herbicide paraquat is an environmental factor that may be involved in the etiology of Parkinson's disease (PD). Systemic exposure of mice to paraquat causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta, although paraquat is not selectively incorporated in dopaminergic neurons. Here, we report a contribution of endogenous dopamine to paraquat-induced dopaminergic cell death. Exposure of PC12 cells to paraquat (50μM) caused delayed toxicity from 36 h onward. A decline in intracellular dopamine content achieved by inhibiting tyrosine hydroxylase (TH), an enzyme for dopamine synthesis, conferred resistance to paraquat toxicity on dopaminergic cells. Paraquat increased the levels of cytosolic and vesicular dopamine, accompanied by transiently increased TH activity. Quinone derived from cytosolic dopamine conjugates with cysteine residues in functional proteins to form quinoproteins. Formation of quinoprotein was transiently increased early during exposure to paraquat. Furthermore, pretreatment with ascorbic acid, which suppressed the elevations of intracellular dopamine and quinoprotein, almost completely prevented paraquat toxicity. These results suggest that the elevation of cytosolic dopamine induced by paraquat participates in the vulnerability of dopaminergic cells to delayed toxicity through the formation of quinoproteins.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ezumi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takada-Takatori
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
mesh_terms: D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D015153:Blotting, Western; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006540:Herbicides / Q000633:toxicity*; D007150:Immunohistochemistry; D008995:Monoamine Oxidase / Q000378:metabolism; D016716:PC12 Cells; D010269:Paraquat / Q000633:toxicity*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors
chemical_list: D006540:Herbicides; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D010269:Paraquat; D004298:Dopamine
keywords: Parkinson disease; dopamine; paraquat; quinoprotein; tyrosine hydroxylase