title: The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients.
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.
authors.affiliation: Centre for Addiction and Mental Health (CAMH) and Departments of Psychiatry, Pharmacology, and Toxicology, University of Toronto, Ontario, Canada.
authors.forename: Amandeep
authors.initials: A
authors.lastname: Mann
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Miksys
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kish
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001921:Brain / Q000196:embryology / Q000201:enzymology / Q000254:growth & development; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011180:Postmortem Changes; D055815:Young Adult
chemical_list: D019389:Cytochrome P-450 CYP2D6