TY - JOUR
T1 - The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients
AU - Mann, Amandeep
AU - Miksys, Sharon L.
AU - Gaedigk, Andrea
AU - Kish, Stephen J.
AU - Mash, Deborah C.
AU - Tyndale, Rachel F.
N1 - Funding Information:
Support for this work was provided by a CRC (RFT), CIHR grant MOP97751 , CAMH and the CAMH foundation, the Canada Foundation for Innovation (#20289 and #16014), and the Ontario Ministry of Research and Innovation.
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - Aging
KW - CNS drugs
KW - CYP2D6
KW - Human brain
KW - Parkinson's disease
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U2 - 10.1016/j.neurobiolaging.2011.08.014
DO - 10.1016/j.neurobiolaging.2011.08.014
M3 - Article
C2 - 21958961
AN - SCOPUS:84859065441
VL - 33
SP - 2160
EP - 2171
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 9
ER -