Differential effects of dopamine melanin on norharman-induced toxicity in PC12 cells.
The food contaminant norharman structurally resembles MPTP a compound that selectively damages pigmented brain areas. Both compounds are sequestered and retained in melanin-containing neurons. The aim of the study was to examine whether intracellular melanin can modulate the toxicity of norharman in melanin-loaded PC12 cells. Dopamine melanin protected against norharman-induced upregulation of grp78, activation of caspase 3 and necrosis at low concentrations (5 and 50 microM). In contrast, at a high conentration (500 microM) there was a significantly increased expression of grp78, hsp90 and caspase 3 and a disassociation of melanin aggregates leading to dispersal of granules to swollen neurite terminals. In human populations, a long-term low-level exposure to toxicants with a high affinity to melanin will probably result in accumulation in melanin-containing neurons in vivo. Our data suggest that accumulation of a neurotoxicant in melanin-loaded cells may lead to increased cell stress, apoptotic signaling and disassociation of melanin aggregates.
Ostergren
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A
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Lindquist
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NG
Brittebo
E B
EB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002243:Carbolines; D053148:Caspase 3 / Q000096:biosynthesis; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis; D006247:Harmine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D008543:Melanins / Q000172:deficiency / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002243:Carbolines; D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008543:Melanins; D009498:Neurotoxins; C081789:dopamine melanin; D006247:Harmine; C010262:norharman; C505410:Casp3 protein, rat; D053148:Caspase 3