1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (
MPTP) is a dopaminergic toxin which produces
Parkinson's disease-like symptoms in primates and dopaminergic cell loss in mice.
MPTP is bioactivated through
monoamine oxidase to MPP(+) and detoxified by
cytochrome P450 to nor-
MPTP. We have examined metabolisms of
MPTP to nor-
MPTP by mouse brain microsomes and compared it with corresponding activity in liver. In brain, but not in liver, this biotransformation was completely abolished by
quinidine, an inhibitor of P4502D. Northern blotting experiments demonstrated constitutive expression of
cytochrome P4502D
mRNA predominantly in neuronal cells within the cortex, hippocampus, thalamus, Purkinje and granule cell layers of the cerebellum and in the reticular neurons of midbrain. Striatal neurons were sparsely stained indicating a relative paucity of expression. These studies demonstrate for the first time that detoxification of
MPTP to nor-
MPTP occurs in mouse brain through
cytochrome P4502D which is primarily localized in neuronal cells.
Cytochrome P4502D6 is known to exhibit genetic polymorphism in humans, and a defect in this
isoform could potentially lead to decreased detoxification of
neurotoxins in certain neuronal sub-population, which in turn may have implications in pathogenesis of
Parkinson's disease.