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

The fact that CYP2D6 is not only expressed in liver but also in brain and the clinical association of this cytochrome with Parkinson's disease suggests the possibility of existence of some endogenous substrate, and among these perhaps one or more neurotransmitters could be metabolized by CYP2D6. In this study we explored such a possibility by studying the modulation of CYP2D6 activity by several neurotransmitters. Our findings confirm the occurrence of a competitive inhibition of dextromethorphan O-demethylation in the presence of tryptamine, with a Ki value of 44.6 microM. Tryptamine was metabolized in human liver microsomes by an enzyme activity with a K(m) of 3.6 +/- 0.9 microM. Such activity is NADPH dependent and is inhibited by quinidine and CYP2D6-specific substrates. The product of the reaction is tryptophol. These results suggest that tryptamine may be an endogenous substrate of CYP2D6.
 ...
PMID:Tryptamine: a possible endogenous substrate for CYP2D6. 917 Jan 45

The cytochrome P450 mono-oxygenase gene, CYP2D6 on chromosome 22q13 (ch22q13), has been inconsistently associated with Parkinson's disease. Associations with CYP2D6 have either been absent altogether or have involved more than one polymorphism, many of which have the same metabolic effect on gene expression. We examined the association between CYP2D6 polymorphisms and Parkinson's disease in a case-control study and included 10 polymorphic dinucleotide repeat markers linked to CYP2D6 to determine whether the association was present or due to linkage disequilibrium. There was no association between any polymorphism of CYP2D6 and Parkinson's disease, but two of 10 dinucleotide repeat markers linked to CYP2D6 were associated with the disease. These results provide evidence to suggest that there may be an unidentified locus for susceptibility to Parkinson's disease that is in linkage disequilibrium with dinucleotide repeat markers mapping near CYP2D6 on ch22q13.
 ...
PMID:Is there a genetic susceptibility locus for Parkinson's disease on chromosome 22q13? 918 44

Recent reports have shown an association between cytochrome P450IID6 (CYP2D6) polymorphism and Parkinson's disease. We investigated the association between this polymorphism and the risk for developing essential tremor (ET). Leukocytic DNA from 91 unrelated ET patients and a control group of 258 unrelated healthy individuals was studied for the occurrence of eight different CYP2D6 allelic variants by using allele-specific PCR amplification Xbal and EcoRI-RFLP's analyses. The prevalence for these allelic variants in the ET and control groups were, respectively: CYP2D6*1 76.9 and 78.7%, CYP2D6*2 0.5 and 0.2%, CYP2D6*3 0 and 1%, CYP2D6*4 12.1 and 12.2%, CYP2D6*5 1.6 and 1.7%, CYP2D6*9 4.4 and 2.9%, CYP2D6*2x2 4.4 and 3.2%. The prevalence of subjects with absent CYP2D6 activity (those carrying two defect genes) was 1.1 and 3.1% in ET and control groups, respectively. Both groups studied were in Hardy-Weinberg equilibrium. These results indicate that mutations at the CYP2D6 gene do not seem to be a major factor in determining susceptibility to ET, and reinforces the view that ET and parkinsonism are distinct conditions.
 ...
PMID:CYP2D6 polymorphism is not associated with essential tremor. 928 32

To further investigate the association between Parkinson's disease (PD) and genetic polymorphism of the CYP2D6 gene, a mutant allele (CVP2D6J) frequently observed in the Japanese population and related to EM/PM polymorphism (phenotypically, individuals are either extensive metabolizers [EM] or poor metabolizers [PM] of debrisoquine) was investigated. The CYP2D6J gene with a nucleotide substitution from C to T at position 188 (the HphI site in exon 1), which reduces CYP2D6 enzyme activity, was analyzed by polymerase chain reaction (PCR) and by digestion with HphI. No significant relationship was observed between PD patients and controls for this mutation. This suggests that the EM/PM polymorphism of CYP2D6 contributes little to the pathogenesis of PD. To further study the molecular basis for the relationship between PD and CYP2D6, the heterogeneity of CYP2D6 was investigated by combined genotype analysis of the two mutant CYP2D6 genes (ie, CYP2D6J, the HphI site mutation in exon 1, and CYP2D6L, the HhaI site mutation in exon 6). Although some characteristic patterns of the combined genotypes were observed in both PD patients and controls, a strong association between the heterogeneity of the CYP2D6 gene and PD was not shown by combined genotype analysis.
 ...
PMID:Genetic analysis of the CYP2D6 gene in patients with Parkinson's disease. 944 Apr 84

Environmental or endogenous toxins may cause nigral cell death in Parkinson's disease (PD) as a result of genetic susceptibility conferred by altered expression of P450 enzymes. Attention over the last 10 years has focused on CYP2D6 polymorphisms and susceptibility to PD. This review summarizes reports arising from both phenotypic and genotypic studies involving CYP2D6 and PD. Phenotypic studies have failed to support a link between CYP2D6 and PD. The more powerful genetic studies initially indicated a link between CYP2D6B mutations and PD, but critical analysis of the literature and recent studies emerging from independent laboratories fail to confirm this. Mutations in CYP2D6B are also not implicated in familial PD. As yet, there is no conclusive evidence to suggest that CYP2D6 polymorphisms confer susceptibility to PD. Whether polymorphisms in other P450s (for example, CYP1A1 and CYP2E1) are implicated in PD remains to be established.
 ...
PMID:P450 enzymes and Parkinson's disease: the story so far. 953 32

Impaired debrisoquine metabolism resulting from defects in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene has been shown to be associated with the development of Parkinson's disease (PD). We studied two polymorphisms in this gene in 207 Chinese PD patients and 227 control subjects by polymerase chain reaction and restriction analysis. The G to A substitution at position 1934 in the junction of intron 3/exon 4 was detected in one sporadic PD patient and two control subjects, all of whom were heterozygous. The single base deletion at position 2637 in exon 5 was not detected in any of the study subjects. Such rarity of CYP2D6 polymorphism indicates PD in the Chinese population is associated with some other gene defects.
 ...
PMID:Rarity of debrisoquine hydroxylase gene polymorphism in Chinese patients with Parkinson's disease. 961 47

We have cloned and characterized the ACO2 gene on human chromosome 22q13, which encodes the essential iron-dependent metabolic enzyme mitochondrial aconitase. We determined that the ACO2 gene comprises 18 translated exons distributed over approximately 35 kilobasepairs (kbp) of DNA. We have shown that the ACO2 mRNA is 2.7kb in length and is expressed ubiquitously, and we can detect multiple isoforms of the ACO2 protein. As others had reported the existence of biochemically active electrophoretic variants of mitochondrial aconitase, we wished to find common ACO2 gene allozymes, functional polymorphisms that might be associated with susceptibility to human genetic diseases. We looked for ACO2 allozymes by DNA sequencing and genotyping in a population of 217 subjects, many of which had idiopathic Parkinson's disease (IPD). We studied patients with IPD because this movement disorder is thought to arise from defects in neuronal iron and energy metabolism, two properties with which aconitase is involved. Furthermore, reports of associations between alleles of the CYP2D6 locus (nearby on 22q13) and IPD, although inconsistent, indicated that an IPD susceptibility locus might be in strong linkage disequilibrium with CYP2D6. We found three functionally silent single nucleotide polymorphisms (SNPs) present in transcribed sequences that exist in similar frequencies in IPD patients and healthy controls. These ACO2 SNPs are in linkage disequilibrium with each other, providing evidence for distinct ACO2 haplotypes. We have, as yet, not detected polymorphisms that would lead to ACO2 allozymes, nor have we observed differences in ACO2 isoform prevalence or distribution in our population of IPD patients and controls. We conclude it is unlikely that polymorphism in the ACO2 gene or post-translational modification of the enzyme predispose to IPD.
 ...
PMID:Characterization of the human mitochondrial aconitase gene (ACO2). 963 Jun 32

Debrisoquine 4-hydroxylase (CYP2D6) is one of the cytochrome P450 enzyme families that catalyze the breakdown of a variety of exogenous and endogenous compounds. Previous reports have suggested that genetic polymorphisms of debrisoquine 4-hydroxylase are associated with susceptibility to Parkinson's disease (PD) in Caucasians. To determine if CYP2D6 also confers susceptibility to PD in Chinese patients, we carried out a study of genetic association using three polymorphic markers of the CYP2D6 gene, 188C/T, 1934G/A (mutant B), and 4268G/C. No differences of allele or genotype frequencies of these three polymorphisms were detected upon comparison of primary PD patients (n=53) with normal controls (n=94). The 1934A allele (mutant B), which accounts for the majority of poor metabolizers in Caucasians, is extremely rare in Chinese. Our data do not support the suggestion that the CYP2D6 gene is related to PD susceptibility in Chinese.
 ...
PMID:Genetic polymorphism and Parkinson's disease in Taiwan: study of debrisoquine 4-hydroxylase (CYP2D6). 966 75

Studies of associations between the CYP2D6 polymorphism and susceptibility to specific diseases, particularly lung cancer and Parkinsonism, have produced conflicting results with respect to an under or overrepresentation of poor metabolizers. Accordingly, we have re-evaluated this primary research (18 studies on lung cancer and 18 on Parkinsonism) using meta-analysis. For lung cancer, the median odds ratio (OR) was 0.69 (95% confidence interval (CI) 0.52-0.90), which differed significantly from unity (P < 0.007). A trail comprising 3000 patient and an equal number of control individuals would be required to demonstrate that this observation had arisen purely by chance (i.e. OR = 1). For Parkinson's disease, the analysis gave an OR of 1.32 (95% CI 0.98-1.78), which was of borderline statistical significance (P < 0.074). If the only individual study that was statistically significant was excluded, the P-value increased greatly to 0.489. A study of at least 500 patients and an equal number of control individuals giving the same value as the current mean OR of 1.32 would be required to make the overall analysis statistically significant. In summary, poor metabolizers with respect to CYP2D6 show a small decrease in susceptibility to lung cancer compared with extensive metabolizers and its is hard to justify further studies. The relationship between the CYP2D6 polymorphism and lung cancer, as a determinant of individual susceptibility, is not appreciable (OR = 0.69) compared with that between smoking and lung cancer (OR > 11). Nevertheless, the epidemiological impact on the number of poor metabolizers who are protected from lung cancer may be considerable. With regard to Parkinson's disease, additional well designed studies may allow a definitive conclusion, although any risk for poor metabolizers is likely to be small and therefore of questionable clinical significance. An important lesson from the current review of studies is that much time, effort, expense and patient inconvenience might have been avoid if more attention had been paid to appropriate study design particularly in the selection of control groups.
 ...
PMID:Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson's disease. 968 68

An epidemiological study of the environmental and genetic factors as well as the possible interplay between them was conducted among 215 patients with Parkinson's disease and 313 controls in a Chinese population in Hong Kong. In univariate analysis, a regular tea drinking habit was found to be a protective factor, which had not been reported before. Smoking (a protective factor), family history, duration of pesticide exposure (in years) in farming and pesticide exposure during farming in women (both risk factors) have been reported previously. In multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. By contrast with the common occurrence of polymorphism of the CYP2D6 gene (a gene involved with xenobiotic metabolism) in white people, it is very rare in China and is not thought to be a significant factor contributing to Parkinson's disease in Chinese people.
 ...
PMID:Genetic and environmental risk factors for Parkinson's disease in a Chinese population. 981 Sep 58


<< Previous 1 2 3 4 5 6 7 8 Next >>