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)

The CYP2D6 polymorphism has been studied extensively in association with Parkinson's disease (PD), with no consistent results. Several explanations, such as differences in study design or bias in the selection of the control population, have been offered for these inconsistent results. We designed a case control study nested within a prospective population-based cohort study in which cases and controls were sampled from the same source population. To assess the significance of the CYP2D6 gene in PD, we investigated two mutant alleles, CYP2D6*3 and CYP2D6*4, associated with poor metabolism and the wild type allele in 80 patients with PD and 156 matched controls, frequency matched on age and gender. No differences between cases and controls were found for the poor metabolizer genotype. However, we found that in contrast to earlier reports, the CYP2D6*4 mutant allele frequency was lower in cases as compared to controls, albeit not statistically significant. Our result supports the hypothesis that the CYP2D6 gene is not a major gene responsible for PD.
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PMID:CYP2D6 polymorphism in Parkinson's disease: the Rotterdam Study. 1129 83

In view of conflicting data in the literature regarding the enzyme(s) responsible for metabolism of selegiline, a drug used in the treatment of Parkinson's disease, investigations were carried out in vitro using the human cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes used, desmethylselegiline and levomethamphetamine were formed from selegiline at significant rates. The highest contribution to the hepatic clearance of selegiline was calculated to be exerted by CYP2B6 (124 l/h) CYP2C19 (82 l/h), whereas CYP3A4 (27 l/h) and CYP1A2 (21 l/h) were of less importance. Antibodies against CYP2B6 inhibited metabolism of selegiline in microsomes containing CYP2B6 but not in microsomes without significant amounts of the enzyme. In contrast to previous reports, we could not find any role for CYP2D6 in the metabolism of selegiline. The data strongly indicate that the high extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2B6 and CYP2C19.
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PMID:CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes. 1160 25

Debrisoquine 4-hydroxylase (CYP2D6) is one of the cytochrome P450 enzyme families that metabolize many compounds. Polymorphic activities of debrisoquine 4-hydroxylase were suggested to be associated with some complex diseases, such as cancer and Parkinson's disease. Schizophrenia is also a complex disorder, and hence we are interested in understanding if the CYP2D6 gene is a susceptibility gene for schizophrenia in Chinese. We determined the genotype and allele frequencies of four molecular variants of CYP2D6 gene (i.e. 188C/T, 1934G/A, 2938C/T and 4268C/G) in 162 Chinese schizophrenic patients and 94 non-psychotic control subjects from Taiwan. No significant differences of allele or genotype frequencies of three polymorphisms (i.e. 188T/C, 2938C/T and 4268C/G) were detected between patients and control subjects. The 1934A allele, which accounts for the majority of poor metabolizers in Caucasians, was not detected in either patients or control subjects, indicating that the 1934A allele is very rare in Chinese. Our data suggest that the CYP2D6 gene may not be a susceptibility gene for schizophrenia in Chinese schizophrenic patients.
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PMID:Debrisoquine 4-hydroxylase (CYP2D6) genetic polymorphisms and susceptibility to schizophrenia in Chinese patients from Taiwan. 1170 57

Factors underlying pathogenesis of diseases are currently being searched. In recent years increasing number of reports on genetic background of central nervous system diseases have appeared. In the search of factors that can precipitate degeneration of dopaminergic neurons the role of enzymes catabolising xenobiotics (CYP2D6, NAT2) and enzymes metabolising catecholamines (COMT, MAO B) has been postulated. Polymorphism of genes coding for isotypes characterised by different biological activity could be responsible for the propensity for Parkinson's disease, progression and efficacy of pharmacotherapy of the disease.
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PMID:[Role of gene polymorphism of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), cytochrome P450 2D6 (CYP2D6) and N-acetyltransferase 2 (NAT2) in pathogenesis of Parkinson's disease]. 1205 3

A systematic review was conducted to estimate the pooled risk of smoking for Parkinson's disease in Chinese populations. The four identified case-control studies had odds ratios with 95% confidence intervals nearly or overlapping unity. Pooled odds ratio of these studies was 0.77 with 95% confidence interval 0.60 to 0.97. It was suggested that smoking induces debrisoquine 4-hydroxylase, which is responsible for the metabolism of antipsychotic drugs and the detoxification of certain environmental toxins known to cause dopaminergic neural damage. This could be the explanation of these contradictory results as cytochrome P-450 CYP2D6 debrisoquine hydroxylase gene polymorphism is known to be much lower in Chinese than in Caucasian people. This systematic review raises concerns about generalization of the conclusion previously settled by many cohort and case-control studies.
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PMID:Smoking and Parkinson's disease: explanatory hypothesis. 1242 25

(S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(-)-OSU6162] is a weak dopamine D2 receptor modulator that possesses potential for the treatment of levodopa (L-DOPA)-induced dyskinesias in patients with Parkinson's disease. In this report, incubations with human liver microsomes revealed that (-)-OSU6162 is selectively metabolized via N-dealkylation to yield N-depropyl (-)-OSU6162. Kinetics evidence is presented that the N-depropylation of (-)-OSU6162 in human hepatic microsomes is mediated by multiple cytochrome p450 (p450) enzymes, in particular CYP2D6. This hypothesis is borne out by several lines of in vitro evidence; 1). incubations of (-)-OSU6162 (5 micro M) with hepatic microsomes from a panel of human donors showed that (-)-OSU6162 N-depropylase activity correlated well with CYP2D6-catalyzed dextromethorphan O-demethylase activity but not with other p450 enzyme-specific activities; 2). quinidine, a CYP2D6-specific inhibitor, inhibited (-)-OSU6162 N-depropylation, whereas other p450 enzyme-specific substrates/inhibitors did not significantly inhibit this activity; 3). CYP2D6 possessed highest intrinsic (-)-OSU6162 N-depropylase activity when compared with a battery of recombinant heterologously expressed human p450 enzymes. In addition, the selectivity of (-)-OSU6162 to inhibit six human p450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2E1, CYP2D6 and CYP3A4) was evaluated using an in vitro inhibition screen. Of the enzymes examined, only the activity of CYP2D6 was inhibited by coincubation with (-)-OSU6162. Thus, it is concluded that (-)-OSU6162 is metabolized by several p450 enzymes and that CYP2D6 accounts for the majority of the observed p450 N-depropylase activity in vitro.
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PMID:Multiple cytochrome P450 enzymes responsible for the oxidative metabolism of the substituted (S)-3-phenylpiperidine, (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, in human liver microsomes. 1243 6

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.
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PMID:[Gene diagnosis of Alzheimer's disease and Parkinson's disease]. 1245 76

We present a review on the genetic and environmental factors implicated in the aetiology of Parkinson's disease. The environmental hypothesis was strongly suggested about 20 years ago after the report of a parkinsonian syndrome in young adults that were intoxicated by a neurotoxin called MPTP which selectively destroys nigrostriatal dopaminergic neurons. Several chemical products used in herbicides and pesticides are similar structurally to MPTP, including paraquat, diquat and rotenone. Epidemiological studies have revealed an increased risk for Parkinson's disease with the use of pesticides and herbicides or the consumption of well water in rural areas of industrialised countries. However, it has not been possible to identify any causative environmental chemical agent in the aetiology of Parkinson's disease despite intensive research. Comparatively, the genetic hypothesis of Parkinson's disease has gained considerable interest during the last decade. Epidemiological studies reveal a family history in 10-25 p. cent Parkinson's disease patients. Several large kindreds with autosomal dominant Parkinson's disease associated with mutations of alpha-synuclein gene (PARK 1) were recently described. alpha-synuclein is a constituant of Lewy bodies, the hallmark of idiopathic Parkinson's disease. However, alpha-synuclein gene mutations are rare as opposed to parkin gene mutations (PARK 2), which are frequently found in autosomal recessive and sporadic young onset Parkinson's disease patients. Other genes or locus are implicated in autosomal dominant familial cases (PARK 3, 4 and 5). Nevertheless, a pure genetic origin can be demonstrated only in a minority of Parkinson's disease patients. Investigation of the possible interaction between genes and environment and of several candidate genes gave contradictory results, notably concerning the association between allelic variants of CYP2D6 gene and the occurrence of Parkinson's disease. In conclusion, the aetiology of Parkinson's disease remains unknown. There are probably several types or causes of Parkinson's disease. In most cases, this heterogeneity could be attributed both to genetic and environmental factors.
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PMID:[Genetic and environmental factors of Parkinson's disease] 1269 Mar 11

We present a review on the genetic and environmental factors implicated in the aetiology of Parkinson's disease. The environmental hypothesis was strongly suggested about 20 years ago after the report of a parkinsonian syndrome in young adults that were intoxicated by a neurotoxin called MPTP which selectively destroys nigrostriatal dopaminergic neurons. Several chemical products used in herbicides and pesticides are similar structurally to MPTP, including paraquat, diquat and rotenone. Epidemiological studies have revealed an increased risk for Parkinson's disease with the use of pesticides and herbicides or the consumption of well water in rural areas of industrialised countries. However, it has not been possible to identify any causative environmental chemical agent in the aetiology of Parkinson's disease despite intensive research. Comparatively, the genetic hypothesis of Parkinson's disease has gained considerable interest during the last decade. Epidemiological studies reveal a family history in 10-25 p. 100 Parkinson's disease patients. Several large kindreds with autosomal dominant Parkinson's disease associated with mutations of alpha-synuclein gene (PARK 1) were recently described. alpha-synuclein is a constituant of Lewy bodies, the hallmark of idiopathic Parkinson's disease. However, alpha-synuclein gene mutations are rare as opposed to parkin gene mutations (PARK 2), which are frequently found in autosomal recessive and sporadic young onset Parkinson's disease patients. Other genes or locus are implicated in autosomal dominant familial cases (PARK 3, 4 and 5). Nevertheless, a pure genetic origin can be demonstrated only in a minority of Parkinson's disease patients. Investigation of the possible interaction between genes and environment and of several candidate genes gave contradictory results, notably concerning the association between allelic variants of CYP2D6 gene and the occurrence of Parkinson's disease. In conclusion, the aetiology of Parkinson's disease remains unknown. There are probably several types or causes of Parkinson's disease. In most cases, this heterogeneity could be attributed both to genetic and environmental factors.
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PMID:[Genetics and environmental factors of Parkinson disease]. 1269 Jun 60

Genetic factors seem to play an important role in the development of Parkinson's disease. The degeneration of the sustantia nigra, characteristic of this disease, might be due to the toxic effect of substances derived from cellular metabolism. The CYP2D6 gene codifies for the metabolising enzyme debrisoquie-4-hydroxilase involved in the detoxification of part of these products. The presence of determinate mutations in the gene implies a lack of enzymatic activity and generates the "poor metaboliser" phenotype. By means of the PCR-RFLP technique, the presence of the genetic mutations CYP2D6 3, CYP2D6 4, CYP2D6 6 and CYP2D6 8 has been analysed in a group of 46 patients with PD and in 54 controls, with the aim of studying the possible value of genotype CYP2D6 as a risk factor for Parkinson's disease in the population of Navarra. The alleles CYP2D6 3, 6 and 8 are not represented in the sample studied. We have not obtained a greater presence of CYP2D6 4 mutations in the patients with respect to the controls (30.43% vs. 44.44%). There is no correlation between Parkinson's disease and the presence of CYP2D6 4 mutations (odds ratio 0.55; 95% CI 0.24 to 1.25), in homozygosis (odds ratio 0.38; 95% CI 0.04 to 3.76) or in heterozygosis (odds ratio 0.62; 95% CI 0.27 to 1.44). In conclusion, the genotype CYP2D6 does not constitute a risk factor in PD.
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PMID:[Prevalence of CYPD6 mutations in sporadic Parkinson's disease: case-control study]. 1286 Dec 92


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