Role of CYP2E1 in the mouse model of MPTP toxicity.

ABSTRACT

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.