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.

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder with a poorly characterized etiopathology. While aging is a substantial risk factor for developing PD (Grosset et al., 2009, Lang and Lozano, 1998), individuals that are either genetically predisposed and/or exposed to endogenous or environmental neurotoxins may have accelerated central nervous system (CNS) damage leading to PD. It has been proposed that individuals with genetic variants in the CYP2D6 gene, encoding a nonfunctional enzyme, have an increased risk for PD which is further increased with exposure to pesticides (Deng et al., 2004, Elbaz et al., 2004, McCann et al., 1997).

Cytochrome P450 2D6 (CYP2D6) can inactivate neurotoxins such as 1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine (MPTP; Modi et al., 1997), 1,2,3-tetrahydroisoquinolines (Suzuki et al., 1992), and β-carbolines (Yu et al., 2003). Furthermore, CYP2D6 can metabolize neurotransmitters including dopamine and serotonin, plus a variety of CNS-acting drugs including antidepressants, analgesics, and antipsychotics (Wang et al., 2009). Importantly, functional CYP2D6 is expressed in the brain notably within the basal ganglia, a primary area affected in PD (Bromek et al., 2010, Mann et al., 2008, Tyndale et al., 1999). Altering CYP2D6 expression and activity in neurological cell lines can influence 1-methyl-4-phenylpyridinium (MPP⁺) neurotoxicity; high levels of CYP2D6 are neuroprotective while low levels reduce the neuroprotection (Mann and Tyndale, 2010, Matoh et al., 2003; Matoh et al., 2003). Thus CYP2D6 may play an important role in localized CNS toxin inactivation, which is of particular relevance in PD.

CYP2D6 is genetically polymorphic resulting in large interindividual variability in expression. Brain CYP2D6 protein levels are further influenced by environmental factors (e.g., smoking) unlike CYP2D6 in the liver (De Gregori et al., 2010, Mann et al., 2008). This variability may affect susceptibility of individuals to environmental neurotoxins altering their risk for developing PD. Here we genotyped for multiple CYP2D6 alleles, measured the ontogenic development of CYP2D6 in the frontal cortex, and determined brain CYP2D6 protein levels in PD cases and age-matched controls.