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CYP 2E1 mutant mice are resistant to DDC-induced enhancement of MPTP toxicity
C Viaggi1, F Vaglini, C Pardini
1Department of Neuroscience, Section of Pharmacology, University of Pisa and Center of Excellence 'AMBISEN' for the Study of Environmental Toxins and CNS Diseases, Pisa, Italy.
Abstract:
In order to reach a deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, we showed that CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. Furthermore we showed that CYP 2E1 is present in the brain and in the basal ganglia of mice (Vaglini et al., 2004). However, because DAS and PIC are not selective CYP 2E1 inhibitors and in order to provide direct evidence for CYP 2E1 involvement in the enhancement of MPTP toxicity, CYP 2E1 knockout mice (GONZ) and wild type animals (SVI) of the same genetic background were treated with MPTP or the combined DDC + MPTP treatment. In CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity, although enhancement of MPTP toxicity was regularly present in the SVI control animals. The immunohistochemical study confirms our results and suggests that CYP 2E1 may have a detoxifying role.
Insights
Diethyldithiocarbamate (DDC) enhances MPTP toxicity by involving CYP 2E1. In CYP 2E1 knockout mice, this enhancement was absent, suggesting CYP 2E1 plays a protective role against MPTP neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that selectively damages dopaminergic (DA) neurons.
- Diethyldithiocarbamate (DDC) is known to enhance MPTP neurotoxicity.
- Cytochrome P450 2E1 (CYP 2E1) is expressed in the brain and basal ganglia.
Purpose of the Study:
- To elucidate the role of CYP 2E1 in DDC-induced enhancement of MPTP neurotoxicity.
- To investigate whether CYP 2E1 has a direct role in potentiating MPTP toxicity.
Main Methods:
- Treatment of wild-type (SVI) and CYP 2E1 knockout (GONZ) mice with MPTP alone or in combination with DDC.
- Immunohistochemical analysis to confirm neuronal damage.
Main Results:
- DDC pretreatment significantly enhanced MPTP toxicity in wild-type SVI mice.
- In CYP 2E1 knockout mice, DDC pretreatment failed to enhance MPTP toxicity.
- Immunohistochemistry confirmed these findings, indicating a protective role for CYP 2E1.
Conclusions:
- CYP 2E1 is critically involved in the DDC-mediated enhancement of MPTP neurotoxicity.
- The results suggest that CYP 2E1 may play a detoxifying role in the context of MPTP toxicity, rather than contributing to its enhancement.
