Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Polymorphism of CYP2D6 and its relationship with the development of Parkinson's disease (PD) has been controversial. The distribution of the B-mutation of CYP2D6, a mutation that results in the absence of a functional protein, differs by ethnicity and accounts for less than 1% of the 'poor metabolizer' phenotype in Asians. Thus, a meta-analysis was conducted to determine if polymorphism, other than the B-mutation, within the CYP2D6 gene confers a greater susceptibility to PD outcome among Asian populations. Eleven studies were identified, two of which were excluded due to unavailability in the English language or availability of the same original data in more detail in another publication. None of the studies showed a statistically significant association between CYP2D6 polymorphism and PD (p<0.05). The overall odds ratio was 0.84 (95% confidence interval 0.66-1.08). We conclude that among Asian populations, there is no convincing evidence of an association between CYP2D6 polymorphism and the risk of developing PD.
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PMID:Parkinson's disease and CYP2D6 polymorphism in Asian populations: A meta-analysis. 1455 87

We performed a case-control study of Parkinson's disease (PD) in a population characterized by a high prevalence of pesticide exposure and studied the joint effect of pesticide exposure and CYP2D6. Although they are based on a small group of subjects with the joint exposure, our findings are consistent with a gene-environment interaction disease model according to which (1) pesticides have a modest effect in subjects who are not CYP2D6 poor metabolizers, (2) pesticides' effect is increased in poor metabolizers (approximately twofold), and (3) poor metabolizers are not at increased PD risk in the absence of pesticide exposure.
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PMID:CYP2D6 polymorphism, pesticide exposure, and Parkinson's disease. 1517 30

The present study was conducted to examine the interaction between cytochrome p450 2D6: CYP2D6 (phase I) poor metabolizer (PM) and glutathione S-transferase M1: GSTM1 (phase II) null genotypes, among 103 unrelated French Parkinson's disease (PD) patients. Both genes are involved in the biotransformation process, and the main objective of that work is to assess synergic effect between CYP2D6 PM and GSTM1 null genotypes in PD patients. Patients with both GSTM1 null genotype and poor metabolizer CYP2D6 have shown a strong dependency of multiplicative interaction (9.50; P = 0.016); this have also been observed when combining GSTM1 null with CYP2D6*4 deficient alleles, but were at the limit of significance (2.18; P = 0.076). Such a combination of polymorphic peculiarities in studied metabolic genes might represent additional risk factor for development of sporadic PD.
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PMID:Interaction between GSTM1-null and CYP2D6-deficient alleles in the pathogenesis of Parkinson's disease. 1506 26

Perhaps one of the most important questions posed by the neurobiology of aging concerns the pathogenic mechanisms in Parkinson's disease (PD). Recently, it was suggested that exposure to pesticides could be the main cause of PD. Another study reported that the environmental endotoxin, lipopolysaccaride produced by Salmonella minnesota, might be a risk factor for PD. An alternative explanation is the genetic component, which has been suggested to be an important risk factor. Epidemiological studies have identified a positive family history of Parkinson as one of the most important risk factors for the disease. However, these studies neither examined nor reviewed the medical records of the family members. The twin study stated that the major factors in the etiology of PD are non-genetic. Meanwhile, epidemiological studies from China have shown that the prevalence of PD is much lower than in the Caucasian population, explained by the low frequency of cytochrome P-450 CYP2D6 debrisoquine hydroxylase gene polymorphism. The etiology of idiopathic PD is still a question for scientists, and calls for further research, especially with the growing proportion of elderly and the rising incidence of PD worldwide. Future research for PD risk factors should consider that multiple interactions occur in PD, resulting in a complex trait, which includes genetic, acquired, and environmental components.
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PMID:Parkinson's disease risk factors: genetic, environmental, or both? 1582 84

Allelic variation at the CYP2D6 gene has been suggested to be associated with CNS disorders, including Parkinson's disease and Lewy body dementia. In order to elucidate whether a relationship exists between CYP2D6 polymorphism and the risk of developing Alzheimer's disease (AD), CYP2D6 allele and genotype frequencies have been evaluated in 94 patients from Southern Italy (29 men and 65 women, aged 74+/-8 years) with AD, and in 350 healthy controls (204 men, 146 women, aged 33+/-9 years) from the same geographical region. Allele frequencies among AD patients were not significantly different from those in healthy controls. Subjects could be divided in four CYP2D6 genotype groups: 52 (56%) patients and 205 (59%) controls carried no mutated alleles (homozygous extensive metabolizers (EM)), 33 (35%) patients and 109 (31%) controls carried one mutated allele (heterozygous EM), while 4 (4%) patients and 11 (3%) controls were found to have two mutated alleles (poor metabolizers (PM)). Five (5%) patients and 25 (7%) controls carried extra copies of a functional gene (ultrarapid metabolizers (UM)). Our results indicate that CYP2D6 polymorphism is unlikely to represent a major risk factor in susceptibility to Alzheimer's disease.
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PMID:No association between CYP2D6 polymorphism and Alzheimer's disease in an Italian population. 1633 9

In the treatment of Parkinson's disease, levodopa, DCI, MAO-B inhibitor, COMT inhibitors, dopamine receptor agonists, amantadine, anticholinergics have been applied and new drugs are being developed. Levodopa is still the golden standard in the treatment of Parkinson's disease. The study on levodopa bioavailability showed 3-4 times differences in individual patients. Drug-food interactions are prominent in levodopa. Low protein food increased levodopa bioavailability and improved no ON or delayed ON in the treatment of Parkinson's disease. Vitamine C or magnesium did not alter the bioavailability of levodopa. The bioavailability of levodopa between the levodopa/carbidioa (100/12.5) group and the levodopa/benserazide (100/25) group was studied in patients with Parkinson's disease by population PK study. C(max) of levodopa in levodeopa/benserazide group was twice as high as in levodopa/carbidopa group. Domperidone, a dopamine receptor antagonist applied as an antiemetic inceases vowel movement. The effect of domperidone on levodopa bioavailability was studied, and the combination of domperidone with levodopa increased AUC of levodopa. Clarythromycin or grape fruit juice inhibits both of CYP3A4 and P-glycoprotein which work on metabolism and absorption of drugs. Coadministration of clarythromycin with ergot alkaloids such as cabergoline or bromocriptine increased the AUC up to 2-3 times. Amantadine is excreted through kidney without being metabolized and renal function is the most important factor in the blood concentration of amantadine. In elder women with the body weight of 50 kg or less, creatinine clearance is less than 50 ml/min even though the serum creatinine is within the normal range. Selegiline is metabolized through CYP2D6 and 3A4. Coadministration of qunidine, cimetidine, maclorides, antifungals, grape fruit juice increase the bioavailability of selegiline and may augment the antiparkinsonian effect.
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PMID:[Inter- and intraindividual pharmacokinetic variations in the treatment of Parkinson's disease]. 1644 56

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin is a chemical inducer of Parkinson's disease (PD) whereas N-methylated beta-carbolines and isoquinolines are naturally occurring analogues of MPTP involved in PD. This research has studied the oxidation of MPTP by human CYP2D6 (CYP2D6*1 and CYP2D6*10 allelic variants) as well as by a mixture of cytochrome P450s-resembling HLM, and the products generated compared with those afforded by human monoamine oxidase (MAO-B). MPTP was efficiently oxidized by CYP2D6 to two main products: MPTP-OH (p-hydroxylation) and PTP (N-demethylation), with turnover numbers of 10.09 min-1 and Km of 79.36+/-3 microM (formation of MPTP-OH) and 18.95 min-1 and Km 69.6+/-2.2 microM (PTP). Small amounts of dehydrogenated toxins MPDP+ and MPP+ were also detected. CYP2D6 competed with MAO-B for the oxidation of MPTP. MPTP oxidation by MAO-B to MPDP+ and MPP+ toxins (bioactivation) was up to 3-fold higher than CYP2D6 detoxification to PTP and MPTP-OH. Several N-methylated beta-carbolines and isoquinolines were screened for N-demethylation (detoxification) that was not significantly catalyzed by CYP2D6 or the P450s mixture. In contrast, various beta-carbolines were efficiently hydroxylated to hydroxy-beta-carbolines by CYP2D6. Thus, N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline (a close MPTP analog) was highly hydroxylated to 6-hydroxy-N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline and a corresponding 7-hydroxy-derivative. Thus, CYP2D6 could participate in the bioactivation and/or detoxification of these neuroactive compounds by an active hydroxylation pathway. The CYP2D6*1 enzymatic variant exhibited much higher metabolism of both MPTP and N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline than the CYP2D6*10 variant, highlighting the importance of CYP2D6 polymorphism in the oxidation of these toxins. Altogether, these results suggest that CYP2D6 can play an important role in the metabolic outcome of both MPTP and beta-carbolines.
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PMID:Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated beta-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6. 1687 Feb 20

The ecogenetic theory contends that most cases of Parkinson's disease (PD) result from the actions of environmental factors in genetically susceptible individuals on a background of normal ageing. This notion is supported by epidemiologic data; family history of PD and exposures to environmental toxins such as pesticides increase risk, while cigarette smoking reduces risk. As a result, polymorphic genes that code for metabolic enzymes have been considered as candidates for conferring differential risk for PD. Given their prominence in xenobiotic metabolism, the cytochrome P450 (CYP) genes have come under great scrutiny. The activity of CYP2D6 is largely determined by genetic variability and common sequence variants exist in human populations that lead to poor metaboliser (PM) phenotypes. These have been extensively studied as genetic risk factors for PD with inconsistent results. However, these studies have disregarded interactive effects (e.g. gene x environment interactions) despite the assertions of the ecogenetic theory. Data from our group and others suggest that the CYP2D6 PM genotype interacts with certain environmental factors such as pesticide exposure and cigarette smoking to confer differential risk for PD. Previous failure to consider such interactions might, in part, explain the inconsistencies observed in the CYP2D6 genetic risk-factor literature. Our data illustrate, using CYP2D6 as an exemplar, that it is crucial to consider both genetic and environmental factors, and their interactions, in any examination of risk factors for PD.
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PMID:CYP450, genetics and Parkinson's disease: gene x environment interactions hold the key. 1701 24

Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by determining individual toxic response variability. In this work, the allelic distributions and genotype associations of three major brain-expressed DMEs were characterized, in sporadic PD cases and controls. No significant association was found between CYP2D6 genotype and PD, but subjects with extensive metabolizer (EM) CYP2D6 phenotype, and the variant GSTP1*B genotype were at significantly higher PD risk than the corresponding poor or intermediary metabolizers (CYP2D6 poor metabolizer phenotype+intermediary metabolizers). A significant association was observed between the GSTP1*B allele and zygosity with PD (GSTP1*A/*B- 51.58%/34.37%, odds ratio (OR) = 2.29; 95% confidence interval (95% CI) = 1.25-4.18; *B/*B- 6.32%/1.05%, OR = 10.67; 95% CI = 1.19-94.79). This association was particularly strong in the elder patients group (> or =69 year) who showed double PD risk for GSTP1*B heterozygous, whilst GSTP1*B/*B homozygous were exclusively found amongst patients. An interaction between GSTM1 and GSTP1 was observed in this late onset PD group. The present results suggest that native GSTP1 encoding the fully active transferase variant should play a relevant role in dopaminergic neuroprotection.
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PMID:Association of A313 G polymorphism (GSTP1*B) in the glutathione-S-transferase P1 gene with sporadic Parkinson's disease. 1725 Jul 23

The aim of the present study was to evaluate the contribution of MAOB, COMT, NAT2 and CYP2D6 gene polymorphisms to early onset Parkinson's disease (PD). The study enrolled 134 patients with Parkinson's disease (early onset-EOPD--67 patients, and late onset--LOPD--patients), and 66 healthy individuals. Polymerane chain reaction restriction fragment length polymorphism (PCR-RFLP) methods were used for genotyping. Univariate analysis revealed a significant two-fold higher EOPD risk among carriers of MAOB allele A or AA genotype. Multivariate analysis revealed that MAOB allele A was an independent factor predisposing to EOPD. It was shown that neither NAT2, CYP2D6 nor COMT genotype was associated with PD.
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PMID:Polymorphisms of catechol-0-methyltransferase (COMT), monoamine oxidase B (MAOB), N-acetyltransferase 2 (NAT2) and cytochrome P450 2D6 (CYP2D6) gene in patients with early onset of Parkinson's disease. 1727 Apr 84


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