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 investigated genetic polymorphism of the cytochrome P-450 CYP2D6 gene from white patients with idiopathic Parkinson's disease (IPD). The mutations of the CYP2D6 gene associated with the poor metabolizer (PM) phenotype of the debrisoquine/sparteine polymorphism were analyzed in DNA of 130 IPD patients by a polymerase chain reaction (PCR)-based DNA amplification combined with Xba I restriction fragment length polymorphism (RFLP) analysis in 105 patients. Another mutation located in exon 6 was analyzed by Hha I RFLP in 94 IPD patients. The frequencies of the different CYP2D6 gene mutations were compared to the frequencies in sex- and age-matched white control population with chronic bronchitis. The rate of genotypically defined PM and the frequencies of the different mutations were not significantly different in IPD patients and controls. These results fail to confirm the previously reported results concerning CYP2D6 gene mutations in IPD. These equivocal results might be related to methodologic problems. However, other hypotheses have been suggested: impairment of neuronal CYP 2D6 expression, transient modification of CYP 2D6 phenotype, or linkage of CYP2D6 gene to the candidate gene locus directly involved in IPD.
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PMID:Lack of relation between genetic polymorphism of cytochrome P-450IID6 and sporadic idiopathic Parkinson's disease. 872 40

Genetic studies of the frequencies of mutant alleles for coding cytochrome P-450 monooxygenase (CYP 2D6) in Parkinson's disease (PD) patients have been inconsistent. We studied the mutants A and B in 80 strictly defined sporadic PD patients divided into young age onset of the disease (< 40 years, N = 20), mid age onset (40-50 years, N = 12), and older age onset (> 50 years, N = 48). They were compared with 108 controls from the same geographic area. There were no significant differences in allele or genotype frequencies between PD patients and controls. Future genetic studies in PD should focus on other alleles or other areas of the genome.
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PMID:Genetic variability of the CYP 2D6 gene is not a risk factor for sporadic Parkinson's disease. 879 39

We investigated genetic polymorphism of the cytochrome P450 CYP 2D6 gene in 105 caucasian patients with idiopathic Parkinson's disease (IPD) and 15 patients with diffuse Lewy body disease (DLBD). The mutations of the CYP 2D6 gene associated with the poor metabolizer (PM) phenotype of the debrisoquine/sparteine polymorphism were analyzed in DNA by a polymerase chain reaction (PCR)-based DNA amplification combined with Xba I restriction fragment length polymorphism (RFLP) analysis. The rate of genotypically defined PM and the frequencies of the mutation D6-B were not significantly different in IPD and DLBD patients. This study fails to find a relationship between CYP 2D6 impairment and neuropathological lesions diffusion in IPD and DLBD. This study cannot exclude involvement of neuronal expression of CYP 2D6.
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PMID:Genetic polymorphism of cytochrome P450 2D6 in idiopathic Parkinson disease and diffuse Lewy body disease. 931 1

We had previously examined environmental, sociodemographic and clinical variables as predictors for Parkinson's disease with dementia (PD + D) and found that lower educational attainment, greater motor impairment and advanced age at disease onset were more common in PD + D than in subjects with Parkinson's disease without dementia (PD-D). We now explore the hypothesis that genetic traits coupled with nongenetic factors may raise the risk of development of PD + D. The study cohort of 43 PD + D and 51 PD-D subjects was analyzed examining environmental, sociodemographic and clinical variables along with 3 candidate gene markers: poor debrisoquine metabolizer allele (CYP 2D6 29B+), monoamine oxidase B allele 1, and apolipoprotein E epsilon 4 allele. Variables were initially entered into a multivariate model singly. Again lower education, age at onset and motor impairment appeared as predictors of PD + D while other variables (including allele status) failed to emerge as significant individual risk factors for dementia. We then examined environmental and genetic variables analyzed in tandem to look for potential variable interactions. Subjects who had pesticide exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted probability of PD + D (stepwise logistic regression model: p = 0.0491). This case-control study provides preliminary evidence that a gene-toxin interaction may play an etiological role in PD + D. Further assessment of the role of these putative risk factors in incident dementia in PD is indicated.
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PMID:Gene-toxin interaction as a putative risk factor for Parkinson's disease with dementia. 959 86

1. The cytochrome P450 monooxygenases, CYP2D6, CYP2C19, and CYP2C9, display polymorphism. CYP2D6 and CYP2C19 have been studied extensively, and despite their low abundance in the liver, they catalyze the metabolism of many drugs. 2. CYP2D6 has numerous allelic variants, whereas CYP2C19 has only two. Most variants are translated into inactive, truncated protein or fail to express protein. 3. CYP2C9 is expressed as the wild-type enzyme and has two variants, in each of which one amino acid residue has been replaced. 4. The nucleotide base sequences of the cDNAs of the three polymorphic genes and their variants have been determined, and the proteins derived from these genes have been characterized. 5. An absence of CYP2D6 and/or CYP2C19 in an individual produces a poor metabolizer (PM) of drugs that are substrates of these enzymes. 6. When two drugs that are substrates for a polymorphic CYP enzyme are administered concomitantly, each will compete for that enzyme and competitively inhibit the metabolism of the other substrate. This can result in toxicity. 7. Patients can be readily phenotyped or genotyped to determine their CYP2D6 or CYP2C19 enzymatic status. Poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (URMs) can be identified. 8. Numerous substrates and inhibitors of CYP2D6, CYP2C19, and CYP2C9 are identified. 9. An individual's diet and age can influence CYP enzyme activity. 10. CYP2D6 polymorphism has been associated with the risk of onset of various illnesses, including cancer, schizophrenia, Parkinson's disease, Alzheimer's disease, and epilepsy.
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PMID:Polymorphic cytochromes P450 and drugs used in psychiatry. 1031 91

Elucidation of the biochemical steps leading to the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-induced degeneration of the nigro-striatal dopamine (DA) pathway has provided new clues to the pathophysiology of Parkinson's Disease (PD). In line with the enhancement of MPTP toxicity by diethyldithiocarbamate (DDC), here we demonstrate how other CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. In order to provide direct evidence for this isozyme involvement, CYP 2E1 knockout mice were challenged with MPTP or the combined treatment. Here we show that these transgenic mice have a low sensitivity to MPTP alone, similarly to the wild type SVI, suggesting that it is likely that transgenic mice compensate for the missing enzyme. However, in these CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity; this enhancement is instead regularly present in the SVI control animals. This study indicates that the occurrence of CYP 2E1 in C57/bl mouse brain is relevant for MPTP toxicity, and suggests that this isozyme may have a detoxificant role related to the efflux transporter of the toxin.
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PMID:Cytochrome P450 and Parkinson's disease: protective role of neuronal CYP 2E1 from MPTP toxicity. 1701 26

Recent advances clarifying the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors that have not been considered in depth lately are discussed. These new data elucidate aspects of enzyme inhibition and pharmacokinetic interactions involving amine oxidases, cytochrome P450 enzymes, aminotransferases (transaminases), and decarboxylases (carboxy-lyases) and the effects of tyramine. Phenelzine and tranylcypromine remain widely available, and many publications have data relevant to this review. Their effect on CYP 450 enzymes is less than many newer drugs. Tranylcypromine only inhibits CYP 450 2A6 (selectively and potently). Phenelzine has no reported interactions, but, like isoniazid, weakly and irreversibly inhibits CYP 450 2C19 and 3A4 in vitro. It might possibly be implicated in interactions (as isoniazid is). Phenelzine has some clinically relevant inhibitory effects on amine oxidases, aminotransferases, and decarboxylases, and it lowers pyridoxal phosphate levels. It commonly causes pyridoxal deficiency, weight gain, sedation, and sexual dysfunction, but only rarely causes hepatic damage and failure, or neurotoxicity. The adverse effects and difficulties with monoamine oxidase inhibitors are less than previously believed or estimated, including a lower risk of hypertension, because the tyramine content in foods is now lower. Potent norepinephrine reuptake inhibitors have a strong protective effect against tyramine-induced hypertension. The newly discovered trace amine-associated receptors probably mediate the pressor response. The therapeutic potential of tranylcypromine and L-dopa in depression and Parkinson disease is worthy of reassessment. Monoamine oxidase inhibitors are not used to an extent proportionate with their benefits; medical texts and doctors' knowledge require a major update to reflect the evidence of recent advances.
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PMID:Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. 2119 46

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD.
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PMID:MAO-inhibitors in Parkinson's Disease. 2211 Mar 57

A strong association between polymorphisms of the cytochrome P450 (CYP/Cyp) 2D6 gene and risk to Parkinson's disease (PD) is well established. The present study investigated the neuroprotective potential of Cyp2d22, a mouse ortholog of human CYP2D6, in maneb- and paraquat-induced parkinsonism and the mechanisms involved therein along with the effects of resveratrol on various parameters associated with Cyp2d22-mediated neuroprotection. The animals were treated intraperitoneally with resveratrol (10mg/kg, daily) and paraquat (10mg/kg) alone or in combination with maneb (30 mg/kg), twice a week, for 9 weeks, along with their respective controls. The subsets of animals were also treated intraperitoneally with a Cyp2d22 inhibitor, ketoconazole (100mg/kg, daily). Maneb and paraquat reduced Cyp2d22 and vesicular monoamine transporter type 2 (VMAT-2) expressions, the number of tyrosine hydroxylase-positive cells, and dopamine content and increased paraquat accumulation in the nigrostriatal tissues, oxidative stress, microglial activation, neuroinflammation, and apoptosis. Cyp2d22 inhibitor significantly exacerbated all these neurodegenerative indexes. Resveratrol cotreatment, partially but significantly, ameliorated the neurodegenerative changes by altering Cyp2d22 expression and paraquat accumulation. The results obtained in the study demonstrate that Cyp2d22 offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration and resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation.
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PMID:Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse. 2233 51

The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.
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PMID:Acetaldehyde and parkinsonism: role of CYP450 2E1. 2380 48


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