Role of CYP2E1 in the mouse model of MPTP toxicity.
It has been shown that diethyldithiocarbamate (DDC) potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice as a result of increased levels of 1-methyl-4-phenylpyridinium ion (MPP(+)) in the striatum. Brain CYP2E1 inhibition by DDC in C57Bl mice was responsible for increased toxicity and striatal MPP(+) accumulation. However, CYP2E1-null mice did not show any enhanced sensitivity to MPTP or any MPP(+) accumulation. This unexpected finding suggested that the CYP2E1-null mice compensate with other isozymes as already described for acetaminophen-induced liver damage. MPP(+) intoxication of mesencephalic cell cultures from CYP2E1-null mice indicated a reduced sensitivity of dopaminergic (DA) neurons from knockout animals. Surprisingly, MPP(+) cell distribution under these conditions indicated that the toxin accumulates more intracellularly in knockout cultures, suggesting further that CYP2E1 has a role in MPP(+) storage and efflux.
Pardini
Carla
C
Department of Neuroscience, Section of Pharmacology, University of Pisa, Via Roma 55, Pisa, Italy.
Vaglini
Francesca
F
Viaggi
Cristina
C
Caramelli
Andrea
A
Corsini
Giovanni U
GU
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
D019392:Cytochrome P-450 CYP2E1; D004298:Dopamine