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)

N-Methyl-4-phenylpyridinium ion (MPP+), a highly toxic metabolite produced in the brain from a street drug contaminant, is selectively taken up by nigrostriatal dopaminergic neurons and accumulated intraneuronally in mitochondria. There it inhibits respiration, causes neuronal death and, in primates, provokes a parkinsonian condition. It has been suggested that endogenously generated or activated agents resembling MPP+ may contribute to the development of Parkinson's disease. We report here that simple beta-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both (2[beta] and 9[indole]) available nitrogens, display mitochondrial inhibitory potencies and neurotoxic effects in vitro (PC12 cultures) and in vivo (striatal microdialysis) which approach or even surpass MPP+. These results take on physiological significance with our finding that brain enzyme activity catalyzes S-adenosylmethionine-dependent methylations of the beta- and indole-nitrogens in beta-carbolines that have been detected in vivo. The unusual 9[indole]-N-methyl transfer, previously unrecognized in animals, apparently requires prior methylation of the 2[beta]-nitrogen. Sequential di-N-methylation of endogenous or xenobiotic beta-carbolines to form unique, neurotoxic 2,9-N,N'-dimethyl-beta-carbolinium ions may serve as a brain bioactivation route in chronic neurodegenerative conditions such as Parkinson's disease.
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PMID:Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins. 161 7

Variations in the activities of xenobiotic metabolizing liver enzymes may be involved in the pathophysiology of diseases, including Parkinson's disease. We therefore studied the activity of the debrisoquine metabolizing enzyme in 97 patients with newly diagnosed Parkinson's disease. The urine debrisoquine metabolic ratios (MR) of the patients were compared with a group of 176 healthy subjects. There were 4 poor metabolizers (4.1%) among the parkinsonians. This proportion did not differ from that found in the group of healthy subjects (51%). In contrast to earlier finding, the parkinsonian poor metabolizers (PM) had the onset of the disease later than the parkinsonian extensive metabolizers (EM). In the parkinsonian patients, it was observed that the excretion of debrisoquine and 4-OH-debrisoquine into urine correlated inversely with the actual age and age at disease onset. Our results indicate that in patients with Parkinson's disease, debrisoquine hydroxylation is comparable with healthy subjects.
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PMID:Debrisoquine oxidation in Parkinson's disease. 203 54

Elevated plasma cysteine to sulphate ratios were found in patients with Motor neurone disease (MND), Parkinson's disease (PD) and Alzheimer's disease (AD). Cysteine and sulphate were measured by colourimetric methods. Following recent discovery of a defect in sulphoxidation and sulphation of xenobiotics in these diseases, this finding confirms that endogenous sulphur metabolism is disturbed. The mean cysteine:sulphate ratios (x 10(3] in fasting early morning plasma were 506, 521 and 477 for MND, PD and AD whereas it was 96 for normal controls (P less than 0.001). This excess of cysteine thiol groups may interfere with neural protein function. The deficiency of sulphate ions may lead to reduced xenobiotic detoxification.
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PMID:Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease. 232 85

Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase MI (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYP1A1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations.
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PMID:Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility. 769 86

The present study examines the psychological characteristics and self-reported responses to xenobiotic agents such as tobacco smoke and pesticide of normal young adults with personality traits similar to those claimed for Parkinsonian patients. Previous research, though controversial, has suggested that persons with idiopathic Parkinson's disease (PD) have premorbid personality traits that may include shyness and repressive defensiveness. Other epidemiological evidence indicates that PD patients may have premorbidly increased prevalence of anxiety, affective, and/or somatoform disorders; decreased rates of smoking and alcohol consumption; and elevated exposure to herbicides or pesticides. A total of 783 college students enrolled in an introductory psychology course completed the Cheek-Buss Scale (shyness), the Marlowe-Crowne Social Desirability Scale (defensiveness), Symptom Checklist 90 (revised), the Mastery Scale, a health history checklist, and rating scales for frequency of illness from alcohol and 10 common environmental chemicals. Subjects were divided into four groups on the basis of above- versus below-median scores on the Cheek-Buss and Marlowe-Crowne scales (persons high in shyness and defensiveness, those high only in shyness, those high only in defensiveness, and those low in both shyness and defensiveness). The group high in shyness but low in defensiveness had the highest, whereas the group low in shyness but high in defensiveness had the lowest, total scores on the SCL-90-R; the two shyest groups were lowest in sense of mastery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Psychological characteristics and subjective intolerance for xenobiotic agents of normal young adults with trait shyness and defensiveness. A parkinsonian-like personality type? 802 35

Proper bodily response to environmental toxicants presumably requires proper function of the xenobiotic (foreign chemical) detoxification pathways. Links between phenotypic variations in xenobiotic metabolism and adverse environmental response have long been sought. Metabolism of the drug S-carboxymethyl-L-cysteine (SCMC) is polymorphous in the population, having a bimodal distribution of metabolites, 2.5% of the general population are thought to be nonmetabolizers. The researchers developing this data feel this implies a polymorphism in sulfoxidation of the amino acid cysteine to sulfate. While this interpretation is somewhat controversial, these metabolic differences reflected may have significant effects. Additionally, a significant number of individuals with environmental intolerance or chronic disease have impaired sulfation of phenolic xenobiotics. This impairment is demonstrated with the probe drug acetaminophen and is presumably due to starvation of the sulfotransferases for sulfate substrate. Reduced metabolism of SCMC has been found with increased frequency in individuals with several degenerative neurological and immunological conditions and drug intolerances, including Alzheimer's disease, Parkinson's disease, motor neuron disease, rheumatoid arthritis, and delayed food sensitivity. Impaired sulfation has been found in many of these conditions, and preliminary data suggests that it may be important in multiple chemical sensitivities and diet responsive autism. In addition, impaired sulfation may be relevant to intolerance of phenol, tyramine, and phenylic food constituents, and it may be a factor in the success of the Feingold diet. These studies indicate the need for the development of genetic and functional tests of xenobiotic metabolism as tools for further research in epidemiology and risk assessment.
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PMID:Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. 871 48

Monoamine oxidase (MAO) plays an essential role in the regulation of various neurotransmitter and xenobiotic amines. Inhibitors of MAO have been employed in the treatment of depression and as adjuncts in Parkinson's disease therapy. X-Band and Q-band electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) spectroscopic techniques are employed to characterize a signal assigned as a stable red anionic semiquinone radical in the resting state of MAO B. It is shown that the radical signal is not affected during substrate (either benzylamine or phenylethylamine) turnover, by anaerobic incubation with substrate, or by covalent modification of the active site flavin cofactor in the catalytically active dimer. Upon denaturation, however, the semiquinone absorbances and EPR signals are lost. Photoreduction of the native enzyme in the presence of ethylenediaminetetraacetate generates an EPR signal that is not the same as that obtained in the resting state and shows different proton ENDOR signals. These results suggest that the two flavin prosthetic groups that exist in catalytically active monoamine oxidase B are physically distinct.
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PMID:Observation of a flavin semiquinone in the resting state of monoamine oxidase B by electron paramagnetic resonance and electron nuclear double resonance spectroscopy. 878 May 11

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.
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PMID:Genetic and environmental risk factors for Parkinson's disease in a Chinese population. 981 Sep 58

Epidemiological studies and case reports provide evidence for an association between Parkinson's disease and past exposure to pesticides. Susceptibility to the effects of pesticides and other putative neurotoxins depends on variability in xenobiotic metabolism possibly generated by genetic polymorphisms, aging and variation in exposure to environmental agents including pesticides. The simplest mechanistic hypothesis for the association of pesticides with Parkinson's disease is that pesticides or their metabolites are directly toxic to mitochondria, although modulation of xenobiotic metabolism by pesticides provides an adjunct or alternative hypothesis.
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PMID:Pesticides and Parkinson's disease. 1034

In the last few years, the genetic contribution to Parkinson's disease has gained major attention and resulted in the identification of four gene loci in autosomal dominant and autosomal recessive Parkinson's disease. Several mutations in two genes have been shown to be responsible for neuronal cell death in Parkinson's disease. One of the gene products involved, alpha-synuclein, is a major component of Lewy bodies, the neuropathological feature of Parkinson's disease. In contrast, mutations in the parkin gene are associated with parkinsonism without Lewy body pathology. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and of xenobiotic metabolism is technically now possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of Parkinson's disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.
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PMID:Genetic influence on the development of Parkinson's disease. 1099 69


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