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

If toxicant exposure contributes to the cause of Parkinson's disease, poor function of detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's disease patients, several have been suggested to be dysfunctional in subgroups, such as those with young age at disease onset. Specific enzymes implicated include several P450 enzymes, most notably P450 IID6, and cysteine dioxygenase. If hepatic enzyme abnormalities contribute to the development of Parkinson's disease, molecular genetic techniques may allow the development of screening tests to identify at-risk subjects in order to intervene with protective therapies.
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PMID:Liver enzyme abnormalities in Parkinson's disease. 189 48

If toxicant exposure contributes to the cause of Parkinson's disease, poor function of detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's disease patients, several have been suggested to be dysfunctional in subgroups, such as those with young age at disease onset. Specific enzymes implicated include several P450 enzymes, most notably P450 IID6, and cysteine dioxygenase. If hepatic enzyme abnormalities contribute to the development of Parkinson's disease, molecular genetic techniques may allow the development of screening tests to identify at-risk subjects in order to intervene with protective therapies.
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PMID:Abnormal liver enzyme-mediated metabolism in Parkinson's disease: a second look. 204 1

It has been suggested that alterations in the activity of cytochrome P450 monooxygenases may play a role in the pathogenesis of Parkinson's disease, particularly in patients who had onset before the age of 40. We studied the P450-mediated metabolism of acetaminophen to 3-hydroxy-acetaminophen in 26 patients with Parkinson's disease and in 18 control subjects. After subjects ingested 1,000 mg acetaminophen, urine was collected under controlled conditions. Acetaminophen and 3-hydroxy-acetaminophen were measured in the urine using newly developed high-pressure liquid chromatography methods. The ratio of 3-hydroxy-acetaminophen to acetaminophen was calculated for each patient and no significant differences were observed in patients compared with control subjects. Abnormal metabolism was not observed in patients who had onset of Parkinson's disease at or before the age of 40. In addition, no difference in metabolic activity was observed between the patients who were treated with levodopa/carbidopa and those who were not treated. These findings suggest that there are no alterations of P450-mediated metabolism of acetaminophen in patients with Parkinson's disease.
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PMID:Acetaminophen metabolism by cytochrome P450 monooxygenases in Parkinson's disease. 277 16

(-)-Deprenyl has been used to irreversibly inhibit monoamine oxidase B (MAO-B) in Parkinson's disease (PD) and Alzheimer's disease (AD) as a possible means of improving dopaminergic neurotransmission or of reducing neuronal necrosis caused by oxidative radical damage. Recent research in tissue culture and animal models has shown that (-)-deprenyl can reduce neuronal apoptosis caused by a variety of agents, in a variety of neuronal subtypes through a mechanism(s) that does not require MAO-B inhibition. Studies using general P450 blockers have shown that one of the principal metabolites of (-)-deprenyl, (-)-desmethyldeprenyl, mediates the antiapoptotic action. Other research has shown that (-)-deprenyl can induce altered expression of a number of genes in preapoptotic neurons both in vitro and in vivo, including the genes for superoxide dismutase (SOD) 1 and 2, BCL-2 and BCL-XL, nitric oxide synthase, c-JUN, and nicotinamide adenine dinucleotide dehydrogenase. Antiapoptosis by (-)-deprenyl is associated with a prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons, which has been shown to occur early in apoptosis and is likely an initiating factor. The above changes in gene expression appear to reduce oxidative radical damage to mitochondria and maintain mitochondrial permeability, thereby blocking mitochondrial "signals" that initiate apoptosis. In situ evidence suggests that apoptosis contributes to neuronal death in a number of neurodegenerative diseases. If apoptosis is critical to the progression of one or more human neurodegenerative diseases, then transcriptionally active agents such as (-)-desmethyldeprenyl may be of value in treating the diseases. The kinetics of (-)-deprenyl metabolism, however, and its biodistribution after oral administration, make it unlikely that the antiapoptotic action has played a major role in benefits found for the drug in PD and AD to date.
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PMID:Modulation of gene expression rather than monoamine oxidase inhibition: (-)-deprenyl-related compounds in controlling neurodegeneration. 895 86

Environmental or endogenous toxins may cause nigral cell death in Parkinson's disease (PD) due to altered expression of P450 enzymes. In rat brain, immunohistochemistry using anti-peptide antisera showed NADPH-P450 oxidoreductase and CYP2B1/2 in various hypothalamic nuclei and CYP1A1 in the globus pallidus, but neither enzyme was expressed in substantia nigra. No specific immunoreactivity to CYP2D1 or CYP3A1 was found in any brain region examined. In contrast, CYP2E1 was expressed in substantia nigra and in striatal blood vessels. Since CYP2E1 is associated with free radical production, it may contribute to the oxidative stress believed to underlie nigral degeneration.
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PMID:Selective localisation of P450 enzymes and NADPH-P450 oxidoreductase in rat basal ganglia using anti-peptide antisera. 901 62

Environmental or endogenous toxins may cause nigral cell death in Parkinson's disease (PD) as a result of genetic susceptibility conferred by altered expression of P450 enzymes. Attention over the last 10 years has focused on CYP2D6 polymorphisms and susceptibility to PD. This review summarizes reports arising from both phenotypic and genotypic studies involving CYP2D6 and PD. Phenotypic studies have failed to support a link between CYP2D6 and PD. The more powerful genetic studies initially indicated a link between CYP2D6B mutations and PD, but critical analysis of the literature and recent studies emerging from independent laboratories fail to confirm this. Mutations in CYP2D6B are also not implicated in familial PD. As yet, there is no conclusive evidence to suggest that CYP2D6 polymorphisms confer susceptibility to PD. Whether polymorphisms in other P450s (for example, CYP1A1 and CYP2E1) are implicated in PD remains to be established.
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PMID:P450 enzymes and Parkinson's disease: the story so far. 953 32

Susceptibility to develop Parkinson's disease has been linked to abnormalities of P450 enzyme function. Multiple P450 enzymes are expressed in brain but the relationship of these to Parkinson's disease is unknown. We have investigated the expression of P450 enzymes in the rat substantia nigra and their co-localization in tyrosine hydroxylase-positive neurons and astrocytes. Immunohistochemistry was performed using anti-peptide antisera against the following P450 enzymes: CYP1A1, CYP1A2, CYP2B1/2, CYP2C12, CYP2C13/2C6, CYP2D1, CYP2D4, CYP2E1, CYP3A1, CYP3A2 and NADPH-P450 oxidoreductase. Immunoreactivity in nigral cells was found only for CYP2E1 and CYP2C13/2C6. CYP2E1 immunoreactivity was localized to many midbrain nuclei including the substantia nigra pars compacta but not the substantia nigra pars reticulata while immunoreactivity to CYP2C13/2C6 was found in the substantia nigra pars compacta, substantia nigra pars reticulata and many other midbrain nuclei. Sections of rat midbrain double labelled for either CYP2E1 or CYP2C13/2C6 and tyrosine hydroxylase or glial fibrillary acidic protein were examined for co-localization by confocal laser scanning microscopy. CYP2E1 and CYP2C13/2C6 immunoreactivity was found in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta but not in glial cells. CYP2C13/2C6, but not CYP2E1, was also found in non-glial, non-tyrosine hydroxylase-expressing cells in the substantia nigra pars reticulata. Isoniazid induction increased CYP2E1 fluorescence signal intensity from nigral dopaminergic neurons. At least two P450 enzymes are found in nigral dopamine containing cells and one, namely CYP2E1, is selectively localized to this cell population. CYP2E1 is a potent generator of free radicals which may contribute to nigral pathology in Parkinson's disease. The expression of CYP2E1 in dopaminergic neurons in substantia nigra raises the possibility of a causal association with Parkinson's disease.
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PMID:Co-localization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase. 988 65

P450 enzymes in the CYP2D subfamily have been suggested to contribute to the susceptibility of individuals in developing Parkinson's disease. We have used specific anti-peptide antisera and peroxidase immunohistochemistry to investigate the expression of CYP2D enzymes in the rat brain and some possible factors that may affect their regulation. In male Wistar rats, CYP2D1 was not detected in the basal ganglia or in any other brain region. CYP2D2 was weakly expressed within neurones of the subthalamic nucleus, substantia nigra and interpeduncular nucleus as well as in the hippocampus, dentate gyrus, red nucleus and pontine nucleus. CYP2D3 and CYP2D4 were absent from the basal ganglia, although moderate amounts of CYP2D3 were detected within fibres of the oculomotor root, and very low levels of CYP2D4 were present in white matter tracts. In contrast, CYP2D5 was extensively expressed in the basal ganglia, including neurones in the subthalamic nucleus, substantia nigra and interpeduncular nucleus, as well as other areas of the brain, including the ventral tegmental area, piriform cortex, hippocampus, dentate gyrus, medial habenular nucleus, thalamic nucleus and pontine nucleus. Lesioning of the nigro-striatal tract to cause almost a complete loss of tyrosine hydroxylase containing neurones in the substantia nigra, also reduced the number of neurones expressing CYP2D5 by 50%, indicating that CYP2D5 is expressed in dopaminergic neurones. Castration of pre-pubertal or adult Wistar rats had no effect on the number of CYP2D5-positive neurones in the substantia nigra. Although Dark Agouti rats lack hepatic CYP2D2, expression in the midbrain was similar to that of Wistar rats; furthermore, there was no difference in expression or distribution between male and female rats. In contrast to naive rats, extensive expression of CYP2D4 was found throughout the basal ganglia and in other brain nuclei in Wistar rats treated with not only clozapine, but also saline, suggesting that CYP2D4 may be induced as a result of mild stress. The function of CYP2D enzymes in the brain remains unknown, but their selective localisation suggests a physiological role in neuronal activity and in adaptation to abnormal situations.
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PMID:Expression and localisation of CYP2D enzymes in rat basal ganglia. 1008 95

The function of cytochrome P450 (P450) in the mammalian brain is not well understood. In an effort to further this understanding, this study identifies two endogenous substrates for P450 2D18. Previous reports have shown that this isoform is expressed in the rat brain, and the recombinant enzyme catalyzes the N-demethylation of the antidepressants imipramine and desipramine. By further examining the substrate profile of P450 2D18, inferences can be made as to potential endogenous P450 substrates. Herein we demonstrate the metabolism of the central nervous system-acting compounds chlorpromazine and chlorzoxazone with turnover numbers of 1.8 and 0. 9 nmol/min/nmol, respectively. Because the four aforementioned pharmaceutical substrates work by binding to neurotransmitter receptors, binding assays and oxidation reactions were performed to test whether dopamine is a substrate for P450 2D18. These data indicate a K(S) value of 678 microM and that P450 2D18 can support the oxidation of dopamine to aminochrome through a peroxide-shunt mechanism. We also report the P450 2D18-mediated omega-hydroxylation and epoxygenation of arachidonic acid, primarily leading to the formation of 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, compounds that have been shown to have vasoactive properties in brain, kidney, and heart tissues. The data presented herein suggest a possible role for P450 involvement in membrane and receptor regulation via epoxyeicosatrienoic acid formation and a potential involvement of P450 in the oxidation of dopamine to reactive oxygen species under aberrant physiological conditions where the sequestering of dopamine becomes compromised, such as in Parkinson's disease.
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PMID:Recombinant cytochrome P450 2D18 metabolism of dopamine and arachidonic acid. 1094 68


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