l‐DOPA Cytotoxicity to PC12 Cells in Culture Is via Its Autoxidation

Abstract: 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.