The neuroprotective enzyme CYP2D6 increases in the brain with age
and is lower in Parkinson’s disease patients
Amandeep Mann et al

Abstract
Cytochrome P450 2D6 (CYP2D6) is a drug-metabolizing enzyme expressed in the brain that also metabolizes endogenous neural
compounds (e.g., catecholamines) and inactivates neurotoxins (e.g., 1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine; MPTP). Genetically poor
CYP2D6 metabolizers are at higher risk for developing Parkinson’s disease (PD), a risk that increases with exposure to pesticides. As age
is a risk factor for PD we measured the ontogenic expression of CYP2D6 in human brain, and compared brain CYP2D6 levels in PD cases
with age-matched controls. CYP2D6 increased from fetal to 80 years of age (n
76), exhibiting 3 distinct phases of change. Compared
with PD controls, PD cases had approximately 40% lower CYP2D6 levels in the frontal cortex, cerebellum, and the hippocampus, even
when controlling for CYP2D6 genotype. In contrast, CYP2D6 levels in cases were similar to controls in PD-affected brain areas, the
substantia nigra, and caudate, consistent with higher astrocytic and cellular CYP2D6 staining observed in PD cases. In summary, the lower
CYP2D6 levels in PD cases may have reduced their ability to inactivate PD-causing neurotoxins contributing to their disease risk.

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