Use of PC12 cells as a neurotoxicological screen: characterization of anticyanide compounds.
A series of six biochemical markers of cyanide toxicity (dopamine release, hydroperoxide generation, cytosolic-free calcium levels, catalase activity, cytochrome oxidase activity, and superoxide dismutase activity) in cultured rat pheochromocytoma (PC12) cells were used to establish a screen for evaluation of potential anticyanide compounds. Thirty-nine substances, including anticonvulsants, adrenergic blockers, antioxidants, and antipsychotics were tested and ranked according to the results. Based on the composite scoring in all six assays, carbamazepine, mannitol, allopurinol, and phenytoin were ranked as the most effective anticyanide compounds. Additionally, known cyanide antidotes (e.g., pyruvate, mercaptopyruvate, alpha-ketoglutarate, naloxone, and flunarizine) obtained relatively high ranking in the PC12 cell screen. Furthermore, a significant correlation was found between protective effects (based on LD50s) of cyanide antidotes in mice and ranking in the in vitro screen. This study illustrates that by assaying a series of biochemical markers in a neuronal-type cell line, a rapid, cost-effective in vitro toxicological screen is possible. Several compounds have been identified which inhibit the biochemical effects of cyanide and may be used to enhance effectiveness of the standard cyanide antidotes.
Borowitz
J L
JL
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907-1334.
Kanthasamy
A G
AG
Mitchell
P J
PJ
Isom
G E
GE
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D000931:Antidotes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002241:Carbohydrates / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors; D003486:Cyanides / Q000633:toxicity*; D003600:Cytosol / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D006861:Hydrogen Peroxide / Q000378:metabolism; D007928:Lethal Dose 50; D051379:Mice; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy; D016716:PC12 Cells / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D013565:Sympatholytics / Q000494:pharmacology; D014116:Toxicology / Q000379:methods
D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D000931:Antidotes; D000975:Antioxidants; D014150:Antipsychotic Agents; D002241:Carbohydrates; D003486:Cyanides; D013565:Sympatholytics; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV; D002118:Calcium; D004298:Dopamine