Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed a case-control study to investigate the association of the poor metaboliser genotype of the cytochrome P450 2D6 gene with Parkinson's disease (PD). Genotyping was determined by the polymerase chain reaction followed by digestion with restriction enzymes. The poor metaboliser genotype was more frequent in 112 patients with PD than in 206 matched controls (odds ratio 1.7, 95% CI: 0.94-2.45). A meta-analysis of these results together with ten other published studies gave a pooled odds ratio for the poor metaboliser genotype of 1.47 (95% CI: 1.18-1.96, P=0.01). Thus, the poor metaboliser genotype has a small but highly significant association with PD which would be easily missed in small studies. Research now should focus on the mechanism of this association.
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PMID:The association between polymorphisms in the cytochrome P-450 2D6 gene and Parkinson's disease: a case-control study and meta-analysis. 945 78

Brain tissue of 50 patients with morphological confirmed Parkinson's disease (PD), blood samples from 149 patients with clinical parkinsonism and from 96 healthy control subjects were collected. Apolipoprotein-E (apo E) and cytochrome P450 2D6 (CYP2D6) genotyping were performed by PCR followed by restriction fragment analysis. A significantly higher allele frequency of CYP2D6*4 was found in patients with PD (35%) but not with parkinsonism (14.1%) compared to control subjects (19.8%). The combined alleles frequency of CYP2D6*3 + apoE4 was significantly higher not only in the PD group (33.3%) but also in patients with parkinsonism (22.3%) compared to control subjects (1.6%). These results suggest that there is a substantial overlap not only in the clinical manifestation but also in the genetic risk factors between Parkinson's and Alzheimer's diseases.
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PMID:Neurogenetic correlates of Parkinson's disease: apolipoprotein-E and cytochrome P450 2D6 genetic polymorphism. 1035 49

Idiopathic Parkinson's disease is a neurodegenerative disorder that affects 1-2% of the population over the age of 65 years. Its aetiology is most likely a combination of complex genetic and environmental factors. Although Mendelian inheritance is seen in less than 5% of cases, recent studies have identified three genes mutations causing Parkinson's disease with a Mendelian inheritance pattern: autosomal dominantly inherited mutations of the alpha-synuclein gene on chromosome 4q21-q23, autosomal recessively inherited mutations of the parkin gene on chromosome 6q25.2-q27 and an autosomal dominantly inherited mutation of the Ubiquitin C-terminal hydrolase L1 (UCH-L1) gene on chromosome 4p14-15.1. A number of other candidate gene polymorphisms including cytochrome P450 2D6, N-acetyltransferase 2, monoamine oxidase-B and glutathione-s-transferase M1 are implicated in sporadic and familial cases and may also play a minor role in the aetiology of Parkinson's disease.
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PMID:Genetics and Parkinson's disease. 1473 67

Alzheimer's disease (AD) and Parkinson's disease (PD) are highly prevalent disorders that account for a large part of the global burden of neurodegenerative diseases. Most AD and PD cases occur sporadically and it is generally agreed that they could arise through interactions among genetic and environmental factors. Candidate genes involved in the metabolism of xenobiotics, neurodegeneration and functioning of dopaminergic neurons were found to be associated with PD. Some of these genes interact with environmental factors that could modify PD risk. Thus, we found that the inverse association between smoking and the risk of PD depended on a polymorphism of the iNOS (inducible NO synthase) gene. We also found that the cytochrome P450 2D6 gene could have a modifying effect on the risk of PD among persons exposed to pesticides. Both interactions have biological plausibility supported by laboratory studies and could contribute to better understand the aetiology of PD. A single susceptibility gene has been identified in sporadic AD. The epsilon4 allele of epsilon polymorphism of the apolipoprotein E gene (APOE) is strongly associated with AD, the risk of AD being multiplied by 5 in persons carrying two epsilon4 alleles. The mechanism of the association between APOE and AD is poorly understood. A few interactions between the epsilon polymorphism and possible risk factors for AD have been described. However, these interactions had no biological plausibility and were likely due to chance.
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PMID:Interaction between genes and environment in neurodegenerative diseases. 1750 88

Evidence, obtained in rodent and primate models of Parkinson's disease (PD) and in preliminary clinical trials, indicates that adenosine A(2A) receptor antagonists might represent a promising non-dopaminergic therapeutic tool for the treatment of PD. Recently, we have reported the biological evaluation of 8-substituted 9-ethyladenines (ANR) as new A(2A) receptor antagonists, three of which (ANR 82, ANR 94, and ANR 152) showed high efficacy in in vivo models for Parkinson's. Understanding the metabolic pathways of new drug candidates is an important aspect of drug discovery. The ANR compounds have been investigated in order to clarify their activity on rat liver microsomes, and more specifically on recombinant human cytochrome P450 2D6 (CYP2D6). The metabolites of all three compounds were detected by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The results indicate that this class of 9-ethyladenines is metabolized only to a fraction of 1.5-5%. These compounds also act as potent mechanism-based inhibitors of CYP450 and in particular of human isoform CYP2D6. Kinetic-analysis of enzyme inactivation was used to describe the effect of these time-dependent inhibitors and to derive the inhibition parameters K(inact) and K(i) defined with respect to the O-demethylation of dextromethorphan.
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PMID:In vitro metabolism studies of new adenosine A 2A receptor antagonists. 1935 9

The present case-control study was carried out to investigate the association of polymorphism in cytochrome P450 2D6 (CYP2D6) and N-acteyltransferase-2 (NAT2}, that are involved in the metabolism and detoxification of chemicals causing Parkinson disease (PD) like symptoms, with PD. Our data demonstrated increased frequency of CYP2D6*2 (1749G/C and 2938C/T), CYP2D6*4 (1934G/A) and CYP2D6*10A (188C/T) polymorphisms in PD cases when compared to the controls. Statistical analysis revealed the significant association of CYP2D6*4 (1934G/A) and CYP2D6*10A (188C/T) polymorphism with PD. Likewise, increased frequency of NAT2*7 polymorphism that leads to the slow acetylator phenotype was observed in PD patients with more than fivefold increased risk (OR: 5.55; 95% CI: 0.56-54). No change was observed in the frequency of NAT*5 or NAT*6 alleles in the cases. Further, cases carrying combination of heterozygous genotypes of CYP2D6*4 or CYP2D6*10A(188C > T) and NAT2*5 were found to be at significantly higher risk for PD demonstrating the importance of gene-gene interactions in determining susceptibility to PD.
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PMID:Association of polymorphism in cytochrome P450 2D6 and N-acetyltransferase-2 with Parkinson's disease. 2036 44

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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PMID:The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients. 2195 61

Parkinson's disease (PD) is the second most common form of neurodegeneration in the elderly population. Clinically, it is characterized by tremor, rigidity, slowness of movement, and postural imbalance. A significant association between low serum vitamin D and PD has been demonstrated, suggesting that elevated vitamin D levels might provide protection against PD. Genetic studies have helped identify a number of proteins linking vitamin D to PD pathology, including the major histocompatibility complex (MHC) class II, the vitamin D receptor (VDR), cytochrome P450 2D6 (CYP2D6), chromosome 22, the renin-angiotensin system (RAS), heme oxygenase-1 (HO-1), poly(ADP-ribose) polymerase-1 gene (PARP-1), neurotrophic factor (NTF), and Sp1 transcription factor. Vitamin D has also been implicated in PD through its effects on L-type voltage-sensitive calcium channels (L-VSCC), nerve growth factor (NGF), matrix metalloproteinases (MMPs), prostaglandins (PGs) and cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), and nitric oxide synthase (NOS). A growing body of evidence suggests that vitamin D supplementation may be beneficial for PD patients. Among the different forms of vitamin D, calcitriol (1,25-dihydroxyvitamin D(3)) is best indicated for PD, because it is a highly active vitamin D(3) metabolite with an appropriate receptor in the central nervous system (CNS).
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PMID:Role of vitamin d in Parkinson's disease. 2261 34

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP(+)), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP(+), as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.
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PMID:Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease. 2325 38

Pseudobulbar affect (PBA) is a common manifestation of brain pathology associated with many neurological diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease, and traumatic brain injury. PBA is defined by involuntary and uncontrollable expressed emotion that is exaggerated and inappropriate, and also incongruent with the underlying emotional state. Dextromethorphan/quinidine (DM/Q) is a combination product indicated for the treatment of PBA. The quinidine component of DM/Q inhibits the cytochrome P450 2D6-mediated metabolic conversion of dextromethorphan to its active metabolite dextrorphan, thereby increasing dextromethorphan systemic bioavailability and driving the pharmacology toward that of the parent drug and away from adverse effects of the dextrorphan metabolite. Three published efficacy and safety studies support the use of DM/Q in the treatment of PBA; significant effects were seen on the primary end point, the Center for Neurologic Study-Lability Scale, as well as secondary efficacy end points and quality of life. While concentration-effect relationships appear relatively weak for efficacy parameters, concentrations of DM/Q may have an impact on safety. Some special safety concerns exist with DM/Q, primarily because of the drug interaction and QT prolongation potential of the quinidine component. However, because concentrations of dextrorphan (which is responsible for many of the parent drug's side effects) and quinidine are lower than those observed in clinical practice with these drugs administered alone, some of the perceived safety issues may not be as relevant with this low dose combination product. However, since patients with PBA have a variety of other medical problems and are on numerous other medications, they may not tolerate DM/Q adverse effects, or may be at risk for drug interactions. Some caution is warranted when initiating DM/Q treatment, particularly in patients with underlying risk factors for torsade de pointes and in those receiving medications that may interact with DM/Q.
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PMID:Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect. 2506 2


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