Dopamine-dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease.
Parkinson's disease is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of this cell death is poorly understood, oxidative stress is thought to play a role. We have previously shown that tetrahydrobiopterin (BH4), an obligatory co-factor for tyrosine hydroxylase (TH), exerts selective toxicity on dopamine-producing cells and that this is prevented by antioxidants. This study shows that BH4-induced dopaminergic cell death is primarily mediated by dopamine, evidenced by findings that (i) BH4 toxicity is increased in proportion to cellular dopamine content; (ii) non-dopaminergic cells become susceptible to BH4 upon exposure to dopamine; and (iii) depletion of dopamine attenuates BH4 toxicity in dopamine-producing cells. BH4 causes lipid peroxidation, suggesting involvement of oxidative stress but the toxicity does not require enzymatic oxidation of dopamine. Instead, it seems to involve formation of quinone product(s) because (i) the cell death is attenuated by exposure to or induction of quinone reductase and (ii) BH4-treated cells show increased formation of protein-bound quinones, which is inhibited by thiol antioxidants. These data taken together suggest that the presence of both BH4 and dopamine is important in rendering dopaminergic cells vulnerable and that this involves formation of reactive dopamine quinone products.
Choi
Hyun Jin
HJ
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Kim
Seong Who
SW
Lee
So Yeon
SY
Hwang
Onyou
O
D000818:Animals; D000975:Antioxidants / Q000633:toxicity; D001708:Biopterins / Q000031:analogs & derivatives* / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011809:Quinones / Q000378:metabolism; D018675:Toxicity Tests; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors
D000975:Antioxidants; D007502:Iron Chelating Agents; D008996:Monoamine Oxidase Inhibitors; D011506:Proteins; D011809:Quinones; D001708:Biopterins; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D016660:NAD(P)H Dehydrogenase (Quinone); C003402:sapropterin; D004298:Dopamine