L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation.
The mechanism of cytotoxicity of L-DOPA was studied in the rat pheochromocytoma PC12 cell line. The cytotoxicity of L-DOPA to PC12 cells was time and concentration dependent. Carbidopa, which inhibited the conversion of L-DOPA to dopamine, did not protect against L-DOPA cytotoxicity in PC12 cells. Furthermore, clorgyline, a selective inhibitor of monoamine oxidase type A, and pargyline, an inhibitor of both monoamine oxidase types A and B, both did not have an effect on L-DOPA toxicity. These findings suggest that cytotoxicity was not due to dopamine formed from L-DOPA. Catalase or superoxide dismutase each partially protected against L-DOPA toxicity in PC12 cells. In combination, the effects were synergistic and provided almost total protection against cytotoxicity. 6-Cyano-7-nitroquinoxaline-2,3-dione, an antagonist of non-NMDA receptors, did not protect against L-DOPA toxicity. These data suggest that toxicity of L-DOPA is most likely due to the action of free radicals formed as a result of its autoxidation. Furthermore, these findings suggest that patients on long-term L-DOPA therapy are potentially at risk from the toxic intermediates formed as a result of its autoxidation.
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Department of Pharmacology, University of Medicine and Dentistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
Morris
E J
EJ
Nicklas
W J
WJ
Geller
H M
HM
D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D007980:Levodopa / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats; D017459:Receptors, Amino Acid / Q000502:physiology; D013482:Superoxide Dismutase / Q000494:pharmacology
D017459:Receptors, Amino Acid; D007980:Levodopa; D002374:Catalase; D013482:Superoxide Dismutase; D004298:Dopamine