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Interactions of manganese with human brain glutathione-S-transferase
A Vescovi1, M Gebbia, G Cappelletti
1Lab. of Neuropharmacology, Neurological Institute C. Besta, Milan, Italy.
Abstract:
Chronic exposure to manganese-laden dusts induces, in humans and lower primates, neurological disorders with clinicopathological features that resemble idiopathic Parkinson's disease. As many authors have suggested, manganese neurotoxicity could be related to the capability of this metal to increase catechol autoxidation in catecholaminergic neurons, therefore increasing the formation of toxic compounds such as peroxides, superoxides, free radicals, and semi-orthoquinones. Oxidative stresses and consequent neuronal damage could then occur if physiological scavenger mechanisms fail in their detoxifying action. We here report that manganese chloride weakly inhibits, in a dose-dependent way by a reversible competitive mechanism, human brain glutathione-S-transferases possibly suggesting that manganese intoxication could cause intraneuronal accumulation of cytotoxic compounds. We also report that both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin known to induce in man Parkinson-like syndromes, and one of its metabolites 1-methyl-4-phenylpyridinium failed to decrease glutathione-S-transferase activity.
Insights
Manganese exposure causes Parkinson-like symptoms by increasing toxic compounds. Manganese chloride inhibits glutathione-S-transferase, potentially leading to harmful intraneuronal buildup.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Chronic manganese exposure causes neurological disorders resembling Parkinson's disease.
- Manganese neurotoxicity is linked to increased catechol autoxidation and reactive oxygen species formation in neurons.
- Impaired cellular defense mechanisms can exacerbate manganese-induced oxidative stress and neuronal damage.
Purpose of the Study:
- To investigate the effect of manganese chloride on human brain glutathione-S-transferase (GST) activity.
- To explore the potential mechanism of manganese neurotoxicity involving GST inhibition.
- To compare the effect of manganese with MPTP and its metabolite on GST activity.
Main Methods:
- In vitro assays measuring human brain glutathione-S-transferase activity in the presence of varying concentrations of manganese chloride.
- Enzyme kinetic analysis to determine the type of inhibition (reversible, competitive).
- Comparative assays using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) to assess their impact on GST activity.
Main Results:
- Manganese chloride demonstrated weak, dose-dependent, and reversible competitive inhibition of human brain glutathione-S-transferase.
- This inhibition suggests manganese intoxication may lead to the intraneuronal accumulation of cytotoxic compounds.
- Neither MPTP nor its metabolite MPP+ affected glutathione-S-transferase activity in the tested conditions.
Conclusions:
- Manganese chloride's inhibition of glutathione-S-transferase provides a potential mechanism for manganese neurotoxicity.
- Impaired GST function could contribute to the buildup of toxic substances within neurons, leading to Parkinson-like symptoms.
- Further research is warranted to fully elucidate the role of GST in manganese-induced neurodegeneration.