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)

Amphetamine, a CYP2D6 substrate, is widely used by truck drivers, and the extent to which different people metabolize the drug has only been determined in an isolated or reduced number of samples. A gas chromatography-mass spectrometry method is implemented to simultaneously determine amphetamine, methamphetamine, and hydroxyamphetamine in the urine of drug users. This method is a useful contribution to a well-established field. The main improvements are the use of liquid-liquid extraction, the trapping of the amphetamines as their hydrochloride salt, as a solution to the volatility of these analytes, and its application to assess the CYP2D6 metabolic phenotype of amphetamine users, which is innovative. Calibration curves ranged from 125 to 1000 ng/mL and had an r(2) greater than 0.99. The validation data (precision, accuracy, and recovery) shows the reproducibility and selectiveness of the method. The method is applied to determine the metabolic ratio (MR) in 121 urine specimens of federal highway drivers who underwent random mandatory roadside testing for drugs. The statistical analysis of the MR shows the presence of three different groups, which according to the established groups for CYP2D6 and the amount of the drug metabolized, are classified into extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). The biological consequences of these differences in amphetamine metabolism, such as impaired driving, a risk to develop Parkinson's disease, or an addiction, need to be further studied.
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PMID:Determination of amphetamine, methamphetamine, and hydroxyamphetamine derivatives in urine by gas chromatography-mass spectrometry and its relation to CYP2D6 phenotype of drug users. 1738 81

A genetic cause of Parkinson's disease is supported by the occurrence of familial disease with identified gene defects, a increased prevalence in homozygous twin pairs and the existence of family clusters. However, familial Parkinson's disease is an interesting but rare form of the disorder and twin studies indicate that heredity may be one of the factors which contribute to the onset of Parkinson's disease. Similarly, the increased risk of Parkinson's disease in relatives of an affected individual suggests a genetic contribution, but alone this is unlikely to explain the onset of nigral cell degeneration. To account for apparently sporadic cases of Parkinson's disease, an involvement of susceptibility genes has been proposed to explain the inherited component of the disorder. However, to date most studies have failed to identify specific genotypic associations with Parkinson's disease. For example, despite extensive investigation no clear association is known between cytochrome P450 isoenzymes, specifically CYP2D6, and Parkinson's disease. Indeed, a genetic component may not be required to explain sporadic Parkinson's disease since environmental factors are associated with an increased prevalence of the illness and the actions of specific toxins are known to induce nigral cell degeneration. In addition, endogenous toxin formation in the brain leads to a variety of processes which may initiate nigral cell death in Parkinson's disease. However, in all probability both genetic and environmental or toxic components contribute to the occurrence of Parkinson's disease and it is likely that an interaction between these factors results in nigral cell degeneration.
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PMID:Genetic susceptibility and the occurrence of Parkinson's disease. 1859 Nov 37

Cytochrome P450 (CYP) 2D6, an enzyme found in the liver and the brain, is involved in the metabolism of numerous centrally acting drugs (e.g. antidepressants, neuroleptics, opiates), endogenous neurochemicals (e.g. catecholamines) and in the inactivation of neurotoxins (e.g. pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Although CYP2D6 is essentially an uninducible enzyme in the liver, we show that smokers have higher CYP2D6 in the brain, especially in the basal ganglia. In order to determine whether nicotine, a component of cigarette smoke, could increase brain CYP2D, African Green monkeys were treated chronically with nicotine (0.05 mg/kg for 2 days, then 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days s.c., b.i.d.). Monkeys treated with nicotine showed significant induction of CYP2D in brain when compared to saline-treated animals as detected by western blotting and immunocytochemistry. No changes in liver CYP2D were observed in nicotine-treated monkeys. Induction was observed in various brain regions including those affected in Parkinson's disease (PD) such as substantia nigra (3-fold, p = 0.01), putamen (2.1-fold, p = 0.001) and brainstem (2.4-fold, p = 0.001), with the caudate nucleus approaching significance (1.6-fold, p = 0.07). Immunocytochemistry revealed that the expression of CYP2D in both saline- and nicotine-treated monkeys is cell-specific particularly in the cerebellum, frontal cortex and hippocampus. These results suggest that monkey brain expresses CYP2D, which is induced in specific cells and brain regions upon chronic nicotine treatment. Smokers, or those using nicotine treatment, may have higher levels of brain CYP2D6 that may result in altered localized CNS drug metabolism and inactivation of neurotoxins.
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PMID:Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment. 1868 46

The main contributory factors of Parkinson's disease (PD) are aging, genetic factors, and environmental exposure to pesticides and heavy metals. CYP2D22, a mouse ortholog of human CYP2D6, is expected to participate in a chemically induced PD phenotype due to its structural resemblance with CYP2D6. Despite its expected participation in PD, its expression in the nigrostriatal tissues and modulation by the chemicals that induce PD or offer neuroprotection have not yet been investigated. The present study was undertaken to investigate CYP2D22 expression in mouse striatum and to assess its involvement in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD phenotype and nicotine-mediated neuroprotection. The animals were treated intraperitoneally daily with nicotine (1 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg) + nicotine (1 mg/kg) for 2-4 weeks and vice versa, along with respective controls. In some sets of experiments, the animals were treated with ketoconazole (300 mg/kg), a CYP3AH/CYP2D22 inhibitor, along with nicotine and/or MPTP. Tyrosine hydroxylase (TH)-immunoreactivity in the substantia nigra, the expression of nicotinic acetylcholine receptors (nAChRs) alpha6 and alpha4, dopamine content, and 1-methyl-4-phenylpyridinium ion (MPP(+)) level in the striatum were measured to confirm the MPTP-induced PD phenotype and nicotine-mediated neuroprotection. CYP2D22 and nAChRs expressions were measured in the striatum by RT-PCR/western blotting and dopamine level; CYP2D22 catalytic activity and MPP(+) content were determined by high-performance liquid chromatography (HPLC). MPTP increased dopaminergic neuronal degeneration and the striatal MPP(+) level and reduced striatal dopamine content; it attenuated expression/activity of CYP2D22 and nAChRs that were significantly restored in nicotine-treated animals. Ketoconazole reduced the nicotine-mediated increase in CYP2D22 expression and activity, dopamine content, and TH-immunoreactivity. The results indicate the expression of CYP2D22 in mouse striatum and its possible role in the MPTP-induced PD phenotype and nicotine-mediated neuroprotection.
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PMID:The expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease phenotype and nicotine-mediated neuroprotection. 1959 27

The present study was aimed at determining which rat cytochrome P450 (CYP) isoforms are involved in the hydroxylation of tyramine to dopamine and at determining whether the reaction can take place in the brain. Moreover, we examined the relative distribution of the CYP2D subfamily's activity in the rat brain, focusing our attention on dopaminergic structures. The study was conducted with cDNA-expressed CYP isoforms (rat CYP1A1, 2A2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6) and with rat brain microsomes. Of the rat CYP isoforms tested, only CYP2D2, 2D4 and 2D18 (but not CYP2D1) were capable of forming dopamine from tyramine. The rat CYP2D isoforms were less efficient than the human CYP2D6 and the efficiency of both human and rat enzymes was higher for m-tyramine (K(m)=256, 143 and 87 microM; V(max)=0.47, 0.23 and 9.55 pmol/pmolCYP/min for CYP2D4, 2D18 and 2D6, respectively) than for p-tyramine (K(m)=433 and 688 microM, V(max)=0.12 and 0.19 pmol/pmolCYP/min for CYP2D4 and 2D18, respectively). Brain microsomes were able to metabolize tyramine to dopamine. The reaction was inhibited by the CYP2D inhibitor quinine and by anti-CYP2D4 antibodies, which suggests that CYP2D4 is the isoform governing tyramine hydroxylation to dopamine in the rat brain. A relatively high level of CYP2D activity (bufuralol 1'-hydroxylation) was found in the substantia nigra, the cerebellum, the nucleus accumbens and the truncus cerebri. The results are discussed in the context of the likelihood of CYP2D-mediated dopamine synthesis in vivo, the implications for Parkinson's disease and the addiction process.
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PMID:The ability of cytochrome P450 2D isoforms to synthesize dopamine in the brain: An in vitro study. 1981 57

Cytochrome P450 (CYP) 2D6 is an enzyme that is expressed in liver and brain. It can inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroisoquinoline and beta-carbolines. Genetically slow CYP2D6 metabolizers are at higher risk for developing Parkinson's disease, a risk that increases with exposure to pesticides. The goal of this study was to investigate the neuroprotective role of CYP2D6 in an in-vitro neurotoxicity model. SH-SY5Y human neuroblastoma cells express CYP2D6 as determined by western blotting, immunocytochemistry and enzymatic activity. CYP2D6 metabolized 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin and the CYP2D6-specific inhibitor quinidine (1 microM) blocked 96 +/- 1% of this metabolism, indicating that CYP2D6 is functional in this cell line. Treatment of cells with CYP2D6 inhibitors (quinidine, propanolol, metoprolol or timolol) at varying concentrations significantly increased the neurotoxicity caused by 1-methyl-4-phenylpyridinium (MPP+) at 10 and 25 microM by between 9 +/- 1 and 22 +/- 5% (P < 0.01). We found that CYP3A is also expressed in SH-SY5Y cells and inhibiting CYP3A with ketoconazole significantly increased the cell death caused by 10 and 25 microM of MPP+ by between 8 +/- 1 and 30 +/- 3% (P < 0.001). Inhibiting both CYP2D6 and CYP3A showed an additive effect on MPP+ neurotoxicity. These data further support a possible role for CYP2D6 in neuroprotection from Parkinson's disease-causing neurotoxins, especially in the human brain where expression of CYP2D6 is high in some regions (e.g. substantia nigra).
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PMID:Cytochrome P450 2D6 enzyme neuroprotects against 1-methyl-4-phenylpyridinium toxicity in SH-SY5Y neuronal cells. 2034 25

A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.
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PMID:A case-control study of Parkinson's disease and tobacco use: gene-tobacco interactions. 2046 8

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

Polymorphisms of the CYP2D6 gene have been reported in association with susceptibility to Parkinson's disease (PD). In a Japanese population, a HhaI polymorphism in the CYP2D6 gene was associated with a 5.56-fold risk of PD (Tsuneoka et al., 1993). We investigated the frequency of this polymorphism in Caucasian patients with sporadic PD and in healthy controls. Although the frequency of the polymorphism was significantly higher in Caucasians compared with Japanese, there was no association with PD.
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PMID:The HhaI polymorphism in the CYP2D6 gene is not associated with Parkinson's disease in a Caucasian population. 2428 87

The relative role of genetic and environmental factors in the pathogenesis of Parkinson's disease (PD) has been the matter of investigation and debate, especially in the last 30 years. The possible interaction between genetic and environmental factors led to a great number of association studies between single nucleotide polymorphisms (SNPs) of many candidate genes and PD risk. In this study we summarized and critically reviewed the results of studies published on this issue, with especial reference to those reported in the last 5 years. Many studies provided conflicting findings and, when positive associations were identified, associations were weak. Polymorphisms related with activation or detoxification of drugs and xenobiotics, such as CYP1A1, CYP1A2, CYP19A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP2D6, NAT2, GSTM1, GSTM3, GSTO1, GSTP1, PON1, PON2, ABCB1 and ADH genes have not been demonstrated convincingly a definitive association with the risk of developing PD. Nor did polymorphisms in genes related to dopamine or serotonin DRD, DAT, TH, DDC, DBH, MAO, COMT, SLC6A4, MTR, MTHFR, oxidative stress NOQ1, NOQ2, mEPHX, HFE, GPX, CAT, mnSOD, HFE, HO-1, HO-2, NFE2L2, KEAP1, inflammatory processes, ILs, TNF, ACT, NOS, HNMT, ABP1, HRHs, trophic and growth factors BDNF, FGF, or mitochondrial metabolism and function. In addition we analyzed other putative relations and genes associated with monogenic familial PD.Taking together the results of candidate gene association studies and genome wide association studies, only some SNPs of the MAPT, SNCA, HLA and GBA genes seem to be the most likely associated with PD risk.
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PMID:Genomic and pharmacogenomic biomarkers of Parkinson's disease. 2469 31


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