N-METHYL-4-PHENYLPYRIDINIUM (MPP-HEPATOCYTES BY CATECHOLAMINES() POTENTIATES THE KILLING OF CULTURED)

The role of catecholamines in the toxicity of MPTP (N-methyl-4-pheny-1 ,2,3,6-tetrahydropyridine) was explored. The killing of cultured hepat ocytes by dopamine and 6-hydroxydopamine was enhanced following inhibi tion of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a manipulation known to sensitize such cells to an oxidative s tress. The participation of activated oxygen species in the cell injur y under such circumstances was shown by the ability of catalase and th e ferric iron chelator deferoxamine to protect the hepatocytes. The to xicity of catecholamines was also potentiated by the mitochondrial sit e I (NADH dehydrogenase) inhibitor rotenone. MPP+ (N-methyl-4-phenylpy ridinium), the putative toxic metabolite of MPTP is also a site I inhi bitor. Incubation of hepatocytes with MPP+ similarly potentiated the t oxicity of 6-hydroxydopamine, dopamine, and norepinephrine under condi tions where MPP+ alone or catecholamines alone did not kill cells. Hep atocytes that had accumulated dopamine from the medium were killed by a subsequent exposure to MPP+ in the absence of a catecholamine in the medium. Hepatocytes that had not been pretreated with dopamine were n ot affected by the subsequent exposure to MPP+. These data indicated t hat catecholamines render hepatocytes more susceptible to the toxicity of MPP+ and suggest that the presence of catecholamines in specific n eurons in the brain may be related to the selective neurotoxicity of M PTP.