CYP 2E1 mutant mice are resistant to DDC-induced enhancement of MPTP toxicity.
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.
Viaggi
C
C
Department of Neuroscience, Section of Pharmacology, University of Pisa and Center of Excellence 'AMBISEN' for the Study of Environmental Toxins and CNS Diseases, Pisa, Italy.
Vaglini
F
F
Pardini
C
C
Sgadò
P
P
Caramelli
A
A
Corsini
G U
GU
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D006224:Cricetinae; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004050:Ditiocarb / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D008658:Inactivation, Metabolic / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009498:Neurotoxins / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011292:Premedication; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000473:pathology
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D009498:Neurotoxins; D004050:Ditiocarb; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019392:Cytochrome P-450 CYP2E1; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine