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)

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

Oxidative stress may contribute to nigral cell death in Parkinson's disease based on postmortem investigations showing increased iron levels, decreased levels of reduced glutathione (GSH), and impaired mitochondrial function. This leads to oxidative damage because lipid peroxidation is increased in substantia nigra and there is a widespread increase in protein and DNA oxidation in the brain in Parkinson's disease. Nitric oxide (NO) may be one of the free radical species involved in nigral degeneration. NO is involved in the production of hydroxyl radicals resulting from MPP+-induced dopamine efflux in striatum. Mice treated with the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole show reduced toxicity to MPTP and knock-out mice lacking neuronal NOS show decreased MPTP susceptibility. In primates, 7-nitroindazole inhibits MPTP toxicity but this remains controversial because no protection is afforded by the nonspecific NOS inhibitor, L-NAME. Indeed, in Parkinson's disease itself, there is little evidence for nitric oxide's involvement in nigral pathology. A susceptibility factor for the development of Parkinson's disease may involve isoforms of cytochrome P450, some of which are found in the brain. CYP2EI, which is associated with free radical production and the formation of endogenous toxins, is selectively localized in nigral dopamine-containing cells. CYP2E1 metabolizes n-hexane leading to the formation of its neurotoxic metabolite 2,5-hexanedione which may explain cases of solvent-induced parkinsonism. Oxidative processes clearly contribute to the pathology of Parkinson's disease but are probably secondary to some other primary unidentified cause, presumably genetic or environmental. Nevertheless, their involvement may allow therapeutic intervention in the cascade of events associated with the progression of Parkinson's disease.
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PMID:Oxidative mechanisms in nigral cell death in Parkinson's disease. 961 15

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.
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PMID:Rarity of debrisoquine hydroxylase gene polymorphism in Chinese patients with Parkinson's disease. 961 47

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.
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PMID:Genetic polymorphism and Parkinson's disease in Taiwan: study of debrisoquine 4-hydroxylase (CYP2D6). 966 75

The selective serotonin reuptake inhibitors (SSRIs) may occasionally induce extrapyramidal side-effects (EPS) and/or akathisia. This may be a consequence of serotonergically-mediated inhibition of the dopaminergic system. Manifestations of these effects in patients may depend on predisposing factors such as the presence of psychomotor disturbance, a previous history of drug-induced akathisia and/or EPS, concurrent antidopaminergic and/or serotonergic therapy, recent monoamine oxidase inhibitor discontinuation, comorbid Parkinson's disease and possibly deficient cytochrome P450 (CYP) isoenzyme status. There is increasing awareness that there may be a distinct form of melancholic or endogenous depression with neurobiological underpinnings similar to those of disorders of the basal ganglia such as Parkinson's disease. Thus, it is not surprising that some individuals with depressive disorders appear to be susceptible to developing drug-induced EPS and/or akathisia. In addition, the propensity for the SSRIs to induce these effects in individual patients may vary within the drug class depending, for example, on their selectivity for serotonin relative to other monoamines, affinity for the 5-HT2C receptor, pharmacokinetic drug interaction potential with concomitantly administered neuroleptics and potential for accumulation due to a long half-life. The relative risk of EPS and akathisia associated with SSRIs have yet to be clearly established. The potential risks may be reduced by avoiding rapid and unnecessary dose titration. Furthermore, early recognition and appropriate management of EPS and/or akathisia is required to prevent the impact of these effects on patient compliance and subjective well-being. It is important that the rare occurrence of EPS in patients receiving SSRIs does not preclude their use in Parkinson's disease where their potentially significant role requires more systematic evaluation.
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PMID:SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. 969 33

The search for genetic polymorphisms relevant to Parkinson's disease etiology and pathogenesis has been motivated by recent thinking emphasizing the potential significance of gene-environment interactions. Especially influential to this research have been the MPTP model of PD induction, hypotheses concerning oxidative stressor reactions, and epidemiological observations of an inverse relation between cigarette smoking and PD risk. This brief review summarizes trends in genetic polymorphism research, with examples provided by investigations of cytochrome P450 enzymes, monoamine oxidase, superoxide dismutase, and mitochondrial genes.
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PMID:Genetic polymorphisms in Parkinson's disease. 974 23

Following the recent identification of multiple novel mutations and alleles of the cytochrome P450 CYP2D6 gene which cause decreased, increased, or absent enzyme activity, we re-examined the controversial hypothesis of a role of the CYP2D6 polymorphism in Parkinson's disease (PD) susceptibility. For this purpose, a strategy based on PCR-SSCP and RFLP analyses allowing the detection of all known CYP2D6 alleles was performed in DNA from 109 patients with sporadic PD. This strategy was also applied to DNA from 68 members of PD families including 18 affected and 50 unaffected members. Seventeen mutations occurring alone or in various combination on 14 alleles of CYP2D6 have been identified in patients with sporadic PD. Moreover, 12 mutations and nine alleles of the gene have been characterized in members of PD families. No significant difference was observed when the distribution of mutations and alleles of CYP2D6 was compared between the PD patients and 514 control subjects previously analyzed using the same strategy. There was also no difference in the distribution of phenotypes predicted from genotypes between both groups. In addition, when the distribution of CYP2D6 genotypes was compared, no difference between affected and unaffected members of PD families was observed. These data indicate that CYP2D6 polymorphism is not a susceptibility factor to PD.
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PMID:CYP2D6 polymorphism and Parkinson's disease susceptibility. 1009 14

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

The reduction or loss of cytochrome P450 enzyme activity as a result of mutations in the CYP2D6 gene has been suggested as a risk factor for Parkinson's disease (PD). Conflicting results among reported studies of the prevalence of mutations among patients with PD suggested a more comprehensive genotyping and an analysis of the interactions with other suspected risk factors and family history. We determined the frequency of seven CYP2D6 mutations among 109 patients with PD and 110 control subjects. Family history of PD, age of onset, exposure to pesticides or herbicides, and well-water consumption were obtained for all cases. There was no significant difference in frequency between patients with PD and control subjects for any mutant allele and no significant association with family history, onset age, or environmental exposures. We sought to increase the power of our study by combining reports from the literature, choosing allele frequencies as the most informative measure. Although we found variability in reported allele frequencies for control subjects that made a meta-analysis problematic, summing all reports demonstrated no difference in CYP2D6 mutation frequency between patients with PD and control subjects. This comprehensive study of CYP2D6 mutations demonstrates that other genes or shared environmental exposures account for the familial risk of PD.
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PMID:Absence of effect of seven functional mutations in the CYP2D6 gene in Parkinson's disease. 1043 95

Human serum paraoxonase (PON1) is associated with high density lipoprotein (HDL) particles. This enzyme is involved in the metabolism of oxidized lipids and also plays a major role in the metabolism and detoxication of insecticides processed through the cytochrome P450/PON1 pathway. An Arg/Gln (R/Q) substitution at position 192 determines a substrate dependent activity polymorphism. In addition to the effect of the amino acid substitution on rates of hydrolysis of different substrates, there is a large interindividual variability in the amount of PON1 protein in sera that is stable over time. Recently, a number of reports based solely on PON1 genotyping have suggested that in some populations, the PON(R192) allele may be a risk factor for coronary artery disease. Another report notes an increased risk of the PON(R192) allele for Parkinson's disease. We report here the development of a two-dimensional, microtitre plate reader-based enzyme analysis that provides a high-throughput assessment of PON1 status. Population distribution plots of diazoxonase versus paraoxonase activities provides PON1 phenotype and an accurate inference of PON1 genotype. Both are important parameters for determining an individual's PON1 status. The analysis also provides PON1 allele frequencies for specific populations.
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PMID:Determination of paraoxonase (PON1) status requires more than genotyping. 1063 37


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