N-methyl-4-phenylpyridinium (MPP+) potentiates the killing of cultured hepatocytes by catecholamines
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J W Snyder1, G M Alexander, T N Ferraro
1Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
Abstract:
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.
Insights
Catecholamines increase susceptibility to MPTP's toxic effects. This suggests that dopamine and related compounds may contribute to the selective neurotoxicity of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in the brain.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin implicated in Parkinsonism.
- The precise mechanisms underlying MPTP's selective neurotoxicity are not fully understood.
- Catecholamines, such as dopamine, are neurotransmitters potentially involved in cellular processes affected by toxins.
Purpose of the Study:
- To investigate the role of catecholamines in the toxicity of MPTP.
- To explore how catecholamines influence cellular sensitivity to MPTP's toxic metabolite, MPP+ (N-methyl-4-phenyl-pyridinium).
- To determine if catecholamines potentiate oxidative stress-induced cell damage.
Main Methods:
- Cultured hepatocytes were exposed to dopamine and 6-hydroxydopamine.
- Glutathione reductase was inhibited using BCNU to induce oxidative stress.
- Cells were treated with rotenone, an inhibitor of mitochondrial site I.
- Hepatocytes were incubated with MPP+ and various catecholamines under different conditions.
Main Results:
- Inhibition of glutathione reductase enhanced catecholamine toxicity, which was mitigated by catalase and deferoxamine, indicating a role for reactive oxygen species.
- Rotenone potentiated catecholamine toxicity.
- MPP+, a known mitochondrial site I inhibitor, potentiated the toxicity of dopamine, 6-hydroxydopamine, and norepinephrine.
- Hepatocytes pre-loaded with dopamine were killed by MPP+, while unloaded cells were not.
Conclusions:
- Catecholamines sensitize hepatocytes to the toxic effects of MPP+.
- The presence of catecholamines may contribute to the selective neurotoxicity of MPTP observed in specific neurons.
- This interaction highlights a potential mechanism for MPTP-induced neurodegeneration.