N-methyl-4-phenylpyridinium (MPP+) potentiates the killing of cultured hepatocytes by catecholamines.
The role of catecholamines in the toxicity of MPTP (N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) was explored. The killing of cultured hepatocytes by dopamine and 6-hydroxydopamine was enhanced following inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a manipulation known to sensitize such cells to an oxidative stress. The participation of activated oxygen species in the cell injury under such circumstances was shown by the ability of catalase and the ferric iron chelator deferoxamine to protect the hepatocytes. The toxicity of catecholamines was also potentiated by the mitochondrial site I (NADH dehydrogenase) inhibitor rotenone. MPP+ (N-methyl-4-phenyl-pyridinium), the putative toxic metabolite of MPTP is also a site I inhibitor. Incubation of hepatocytes with MPP+ similarly potentiated the toxicity of 6-hydroxydopamine, dopamine, and norepinephrine under conditions where MPP+ alone or catecholamines alone did not kill cells. Hepatocytes 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 not affected by the subsequent exposure to MPP+. These data indicated that catecholamines render hepatocytes more susceptible to the toxicity of MPP+ and suggest that the presence of catecholamines in specific neurons in the brain may be related to the selective neurotoxicity of MPTP.
Snyder
J W
JW
Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
Alexander
G M
GM
Ferraro
T N
TN
Grothusen
J R
JR
Farber
J L
JL
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002395:Catecholamines / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone
D002395:Catecholamines; D012402:Rotenone; D016627:Oxidopamine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine