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)

Microsomal 4-hydroxylase of 1,2,3,4-tetrahydroisoquinoline (TIQ), a possible candidate for causing Parkinson disease, was characterized by using rat hepatic microsomes and purified P450 isozymes. Kinetic analysis revealed that Km and Vmax values (mean +/- SE) for hepatic microsomal TIQ 4-hydroxylase of male Wistar rats were 319.6 +/- 26.8 microM and 12.13 +/- 1.43 pmol.min-1.mg-1 protein, respectively. When TIQ 4-hydroxylase activity was compared in Wistar (an animal model of extensive debrisoquine metabolizers) and Dark Agouti (an animal model of poor debrisoquine metabolizers) rats, significant strain (Wistar greater than Dark Agouti) and sex (male greater than female) differences were observed. The microsomal activity toward TIQ 4-hydroxylation was increased by pretreatment of male Wistar rats with P448 inducers (beta-naphthoflavone and sudan I), but not with phenobarbital. Pretreatment with propranolol, an inhibitor of P450 isozymes belonging to the P450 IID gene subfamily, decreased TIQ 4-hydroxylase activity. P450 BTL, a P450 isozyme belonging to the IID subfamily, showed TIQ 4-hydroxylase activity of 64.1 pmol.min-1.nmol P450(-1), which was 3.2-fold that of microsomes (20.9 pmol.min-1.nmol P450(-1)). Antibody (IgG) against this isozyme suppressed microsomal TIQ 4-hydroxylase activity concentration-dependently. A male-specific P450 ml (P450IIC11) catalyzed this reaction to a much lesser extent (10.0 pmol.min-1.nmol P450(-1)), and its antibody did not affect the microsomal activity. These results suggest that TIQ 4-hydroxylation in hepatic microsomes are catalyzed predominantly by a P450 isozyme (or isozymes) belonging to the IID gene subfamily in non-treated rats and its immunochemically related P450 isozyme (or isozymes), and that a P450 isozyme (or isozymes) belonging to the IA subfamily also participates in TIQ 4-hydroxylation in rats pretreated with P448-inducers.
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PMID:Cytochrome P450 isozymes catalyzing 4-hydroxylation of parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline in rat liver microsomes. 153 68

Degenerative diseases of the nervous system which are considered to be related to free radicals are Parkinson's disease and Alzheimer-type dementia (ATD). Parkinson's disease is characterized by appearance of Leyw's body and degeneration of nigrostriatal dopaminergic system. But the most fundamental cause of this disease remains still unknown. The fact that H2O2 is formed in the process of oxidative deamination of catecholamines and some substances which can cause Parkinsonism in animal experiments also produce active oxygen in the metabolic processes suggest the important role of free radicals in the pathogenesis of Parkinson's disease. We recently observed that addition of DOPA and Fe3(+)-ADP complex to the microsomal phospholipid system produced lipid peroxides without participation of active oxygen. Neurons cultured in vitro also decreased significantly with addition of DOPA and Fe3(+)-ADP complex and this harmful effect was prevented by desferoxamine (potent Fe chelating agent) or alpha-tocopherol (antioxidant). These results may suggest that lipid peroxidation can occur by interaction of naturally existing substances in the dopaminergic system and induce cell damage. As regards ATD, there is still no definite evidence to support the implication of free radicals in its pathogenesis. However, there are reports that lipid peroxides increase significantly in the brains of patients with ATD. Moreover, recent advances in the study of amyloid in the senile plaque revealed close relationship of ATD to chromosome 21.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Free radicals and degenerative diseases of the nervous system]. 220 Sep 16

The localization of adrenergic receptors in the central nervous system was studied in two physiological conditions of noradrenergic denervation, a 6-hydroxydopamine-induced lesion of the locus coeruleus in newborn rat, and a pathological related degeneration of the locus coeruleus in man, Parkinson's disease. The localization of these receptors in the synapse has been studied with the technique of subcellular fractionation by differential centrifugation. In lesioned rats, an increase in the density of alpha 1 and beta 1 receptors was observed in several brain regions, in contrast to alpha 2 receptors which were not modified. Subcellular fractionation in lesioned rats showed an increase in alpha 1 and beta 1 receptors in synaptosomal fractions. Similar results were found in parkinsonian patients: alpha 1 receptors increased in the synaptosomal fraction; beta receptors increased in synaptosomal and microsomal fractions. These results suggest that alpha 1 and beta 1 receptors may be located on non-noradrenergic nerve terminals in mammalian brain. alpha 2 and beta 2 receptors may be situated on glial cells or neuronal elements unrelated to noradrenergic input.
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PMID:Cellular localization of adrenergic receptors in rat and human brain. 308 66

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

Paraquat has been implicated as an environmental toxin which may induce the syndrome of Parkinson's disease after exposure to this agent. However, the biochemical mechanism by which paraquat causes cell death and neurodegeneration has not been extensively studied. Paraquat was rapidly taken up by nerve terminals isolated from mouse cerebral cortices. It induced lipid peroxidation in a concentration dependent manner in the presence of NADPH and ferrous ion. The maximal stimulation effect was obtained at a paraquat concentration around 100 microM and the Km value for paraquat was 46.7 microM. The lipid peroxidation required microsomal enzymes. Antioxidants, such as superoxide dismutase, catalase and promethazine significantly inhibited paraquat-induced lipid peroxidation. Due to its structural similarity to the pyridinium compound MPP+ (N-methyl-4-phenyl pyridium ion), it may be taken up by dopamine neurons and cause lipid peroxidation and cell death resulting in the manifestation of Parkinsonian syndrome.
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PMID:Paraquat-induced free radical reaction in mouse brain microsomes. 948 66

Pathological and biochemical studies have consistently associated endogenous catechol oxidation with dopaminergic neurodegeneration in Parkinson's disease (PD). Recently, it has been proposed that products of catechol oxidation, the catechol thioethers, may contribute to dopaminergic neurodegeneration. In other organ systems, thioether cytotoxicity is influenced profoundly by the mercapturic acid pathway. We have pursued the hypothesis that endogenous catechol thioethers produced in the mercapturic acid pathway contribute to dopaminergic neurodegeneration. Our results showed that the extent of in vitro metal-catalyzed oxidative damage by catechol thioethers varied with the structures of the parent catechol and thioether adduct. Catechol mercapturates uniquely produced more oxidative damage than their parent catechols. In dopaminergic cell cultures, dopamine induced apoptosis in a concentration-dependent manner from 5 to 50 microM. The apoptotic effect of dopamine was greatly enhanced by subcytotoxic concentrations of the mitochondrial inhibitor, N-methyl-4-phenylpyridinium (MPP+). Similarly, subcytotoxic levels of the mercapturate or homocysteine conjugate of dopamine significantly augmented dopamine-induced apoptosis. Finally, microsomal fractions of substantia nigra from PD patients or age-matched controls had comparable cysteine-S-conjugate N-acetyltransferase activity. These data indicate that the mercapturate conjugate of dopamine may augment dopaminergic neurodegeneration and that the mercapturate pathway exists in human substantia nigra.
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PMID:Dopamine mercapturate can augment dopaminergic neurodegeneration. 1113 34

alpha-Synuclein (alphaS) is a 140-residue neuronal protein that forms insoluble cytoplasmic aggregates in Parkinson's disease (PD) and several other neurodegenerative disorders. Two missense mutations (A53T and A30P) are linked to rare forms of familial PD. The normal function of alphaS is unknown, and cultured cell systems that model its modification from soluble monomers to aggregated forms have not been reported. Through a systematic centrifugal fractionation of mesencephalic neuronal cell lines and transgenic mouse brains expressing wild-type or A53T human alphaS, we observed unusual, previously unrecognized species of alphaS that migrate well above the 17-kDa monomeric form in denaturing gels. Incubation at 65 degrees C of high-speed cytosols from cells or brains revealed a modified alphaS species migrating at approximately 36 kDa and an extensive higher molecular mass alphaS-reactive smear. Extraction of the cytosols with chloroform/methanol or with a resin (Lipidex 1000) that binds fatty acids resulted in a similar pattern of higher molecular mass alphaS forms. On the basis of this effect of delipidation, we reexamined the primary structure of alphaS and detected a motif at the N and C termini that is homologous to a fatty acid-binding protein signature. In accord, we found that purified human alphaS binds oleic acid, with an apparent K(d) of 12.5 microM. We also observed an enhanced association of A53T alphaS with microsomal membranes in both mesencephalic cells and transgenic mouse brains. We conclude that alphaS has biochemical properties and a structural motif that suggest it is a novel member of the fatty acid-binding protein family and may thus transport fatty acids between the aqueous and membrane phospholipid compartments of the neuronal cytoplasm.
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PMID:alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. 1148 78

Oxidative stress is hypothesized to play a major role in the destruction of dopaminergic neurons, which is associated with Parkinson's disease. Epoxides are potentially reactive intermediates formed through the oxidative metabolism of both exogenous and endogenous substances that contribute to cytotoxic damage mediated by oxidative stress. The microsomal (EPHX1) and soluble (EPHX2) epoxide hydrolases function to regulate the oxidation status of a wide range of xenobiotic- and lipid-derived substrates; therefore, interindividual variation in these pathways may mitigate epoxide-related cellular injury. In this investigation, we examined the potential association between the risk of Parkinson's disease and genetic variation within the EPHX1 and EPHX2 genes. Fluorescent 5' nuclease-based assays were developed to identify the allelic status of individuals with respect to specific single nucleotide polymorphisms in exons 3 and 4 of the EPHX1 gene and exons 8 and 13 of the EPHX2 gene. EPHX1 and EPHX2 genotype data were obtained from 133 idiopathic Parkinson's disease patients and 212 control subjects matched on age, gender and ethnicity. No statistically significant differences were found in the distribution of the reference and variant alleles between Parkinson's disease and control subjects, or when results were stratified by gender. Therefore, common polymorphisms within EPHX1 and EPHX2 do not appear to be important risk factors for Parkinson's disease.
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PMID:Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease. 1169 79

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3-202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3-202 within the active site of COMT and discuss their implication on the regioselectivity of metabolic O-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity of O-methylation of BIA 3-202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivo O-methylation by COMT at either meta or para catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, the p-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolic O-methylation are discussed.
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PMID:Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor. 1258 50

1. The aim was to clarify the kinetic and cytochrome P450 (CYP) enzymes involved in l-deprenyl metabolism by liver microsomal preparations from African green monkeys, an animal model extensively used in the study of Parkinson's disease. 2. CYP levels and monoxygenase activities were similar to those observed in microsomes from other monkey strains. The enzyme kinetics of both l-methamphetamine and l-nordeprenyl formation were characterized by a high- and low-affinity component. For l-methamphetamine, the apparent K(m1) and K(m2) were 1.07 +/- 0.01 and 350 +/- 2.7 micro M, and V(max1) and V(max2) were 4.70 +/- 0.01 and 8.9 +/- 0.02 nmol min(-1) mg protein(-1), respectively. For l-nordeprenyl, K(m1) and K(m2) were 0.96 +/- 0.05 and 168 +/- 15 micro M, and V(max1) and V(max2) were 3.34 +/- 0.02 and 3.91 +/- 0.02 nmol min(-1) mg protein(-1), respectively The ratio V(max)/K(m) for both metabolites was 2 orders of magnitude higher for the low K(m) component than for the high K(m), suggesting that the former component is the major determinant of l-deprenyl N-dealkylation. At 15 micro M l-deprenyl, both ketoconazole and 8-methoxypsoralen significantly inhibited l-methamphetamine and l-nordeprenyl formation, indicating that CYP3A and CYP2A enzymes were involved in both reactions. At 500 micro M l-deprenyl, however, inhibition studies suggest the involvement of CYP1A and 2D enzymes. 3. The metabolism of l-deprenyl by monkey liver microsomes is very efficient, indicating that CYP-dependent metabolism is relevant and could contribute to neuroprotection in primate models of Parkinson's disease.
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PMID:l-Deprenyl metabolism by the cytochrome P450 system in monkey (Cercopithecus aethiops) liver microsomes. 1262 60


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