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)

CYP2D, a genetically variable isoform of cytochrome P450, has been characterized mainly in the liver and the brain of mammals by measurement of debrisoquine hydroxylase activity. Moreover, 'poor debrisoquine metabolizer' phenotype is significantly increased in Parkinson's disease patients. We present here the first demonstration that the activity of the CYP2D isoform can be characterized in rat brain microsomes by the measurement of dextromethorphan O-demethylase capacity. The cerebral formation of dextrorphan, an antagonist of the N-methyl-D-aspartate receptor, was inhibited by the presence of quinidine and N-methyl-4-phenylpyridinium (MPP+), a dopaminergic neurotoxin inducing a chemical parkinsonism in humans.
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PMID:Dextromethorphan O-demethylase activity in rat brain microsomes. 761 5

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinson-like syndrome through biotransformation by monoamine oxidase B to the neurotoxic metabolite 1-methyl-4-phenylpyridine. Neuroprotection may be provided by parallel N-demethylation and N-oxidation pathways mediated by the microsomal cytochrome P450 and flavin monooxygenase systems, respectively. The aims of this study were to characterise the N-demethylation of MPTP by human liver microsomes over a wide range of concentrations, and to identify the cytochrome P450 enzymes involved in this reaction. The kinetics of the N-demethylation of MPTP (1 microM - 3 mM) by microsomes from the liver of an extensive metabolizer with respect to cytochrome P4502D6 (CYP2D6) activity were biphasic (apparent Km1 and Km2 values = 48 and 2882 microM). The high affinity activity was abolished in the presence of quinidine (1 microM) and was absent in microsomes from a genotypically poor metabolizer with respect to CYP2D6. Yeast microsomes containing heterologously expressed CYP2D6 N-demethylated MPTP (Km = 39 microM), and there was a high correlation between the quinidine-inhibitable N-demethylation of MPTP (50 microM) (0.7-91%, mean 44%, of total activity) and the alpha-hydroxylation of metoprolol in microsomes from 11 human livers (rs = 0.92; P < .001). At 50 microM MPTP, N-demethylase activity in human liver microsomes was also inhibited by furafylline (10 microM) and ketoconazole (2 microM) (mean inhibition 39 and 13%, respectively; n = 11 livers). Yeast microsomes containing heterologously expressed human CYP1A2 N-demethylated MPTP with a Km of 2246 microM. These findings indicate that CYP2D6, CYP1A2 and, to a lesser extent CYP3A4, may have a role in protecting against Parkinson's disease induced by MPTP and other potential environmental neurotoxins. The data provide some biochemical support for the proposition that genotypically poor metabolizers with respect to CYP2D6 are overrepresented in some populations of Parkinson's patients, and that smokers (induced CYP1A2?) are underrepresented.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2 and 3A4--implications for susceptibility to Parkinson's disease. 862 46

(S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(-)-OSU6162] is a weak dopamine D2 receptor modulator that possesses potential for the treatment of levodopa (L-DOPA)-induced dyskinesias in patients with Parkinson's disease. In this report, incubations with human liver microsomes revealed that (-)-OSU6162 is selectively metabolized via N-dealkylation to yield N-depropyl (-)-OSU6162. Kinetics evidence is presented that the N-depropylation of (-)-OSU6162 in human hepatic microsomes is mediated by multiple cytochrome p450 (p450) enzymes, in particular CYP2D6. This hypothesis is borne out by several lines of in vitro evidence; 1). incubations of (-)-OSU6162 (5 micro M) with hepatic microsomes from a panel of human donors showed that (-)-OSU6162 N-depropylase activity correlated well with CYP2D6-catalyzed dextromethorphan O-demethylase activity but not with other p450 enzyme-specific activities; 2). quinidine, a CYP2D6-specific inhibitor, inhibited (-)-OSU6162 N-depropylation, whereas other p450 enzyme-specific substrates/inhibitors did not significantly inhibit this activity; 3). CYP2D6 possessed highest intrinsic (-)-OSU6162 N-depropylase activity when compared with a battery of recombinant heterologously expressed human p450 enzymes. In addition, the selectivity of (-)-OSU6162 to inhibit six human p450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2E1, CYP2D6 and CYP3A4) was evaluated using an in vitro inhibition screen. Of the enzymes examined, only the activity of CYP2D6 was inhibited by coincubation with (-)-OSU6162. Thus, it is concluded that (-)-OSU6162 is metabolized by several p450 enzymes and that CYP2D6 accounts for the majority of the observed p450 N-depropylase activity in vitro.
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PMID:Multiple cytochrome P450 enzymes responsible for the oxidative metabolism of the substituted (S)-3-phenylpiperidine, (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, in human liver microsomes. 1243 6

In previous studies, we documented increased citrullinated myelin basic protein (MBP) was present in MBP isolated from multiple sclerosis (MS) normal appearing white matter (NAWM). This increase was due to the myelin enzyme peptidyl argininedeiminase 2 (PAD2). In this study, we show that methylation of cytosine of the PAD2 promoter in DNA from MS NAWM was decreased to one-third of the level of that in DNA from normal white matter. The PAD2 promoter in DNA from thymus obtained from the same MS patients and white matter DNA from Alzheimer's, Huntington's, and Parkinson's was not hypomethylated. DNA demethylase activity in supernatants prepared from NAWM of MS patients was 2-fold higher than the DNA demethylase from normal, Alzheimer's, Huntington's and Parkinson's disease white matter. The amount of PAD2 enzyme and citrullinated MBP was increased in MS NAWM. The decreased methylation of cytosines in the PAD2 promoter may explain the increased synthesis of PAD2 protein that is responsible for the increased amount of citrullinated MBP, which in turn results in loss of myelin stability in MS brain.
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PMID:Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. 1746 38

Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.
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PMID:Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson's disease. 2421 61

N6-Methyladenosine (m6A) is the most prevalent internal modification that occurs in the mRNA of eukaryotes and plays a vital role in the post-transcriptional regulation. Recent studies highlighted the biological significance of m6A modification in the nervous system, and its dysregulation has been shown to be related to degenerative and neurodevelopmental diseases. Parkinson's disease (PD) is a common age-related neurological disorder with its pathogenesis still not fully elucidated. Reports have shown that epigenetic mechanisms including DNA methylation and histone acetylation, which alter gene expression, are associated with PD. In this study, we found that global m6A modification of mRNAs is down-regulated in 6-OHDA-induced PC12 cells and the striatum of PD rat brain. To further explore the relationship between m6A mRNA methylation and molecular mechanism of PD, we decreased m6A in dopaminergic cells by overexpressing a nucleic acid demethylase, FTO, or by m6A inhibitor. The results showed that m6A reduction could induce the expression of N-methyl-d-aspartate (NMDA) receptor 1, and elevate oxidative stress and Ca2+ influx, resulting in dopaminergic neuron apoptosis. Collectively, m6A modification may play a vital role in the death of dopaminergic neuron, which provides a novel view of mRNA methylation to understand the epigenetic regulation of Parkinson's disease.
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PMID:Down-Regulation of m6A mRNA Methylation Is Involved in Dopaminergic Neuronal Death. 3083 97