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)

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is maybe initiated or precipitated by environmental or endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. Endogenous analogs of MPTP, such as beta-carbolines (betaCs) and tetrahydroisoquinolines, have been proposed as possible causative candidates causing PD and are bioactivated into potential neurotoxins by N-methylation enzyme(s). These N-methylated betaCs and tetrahydroisoquinoline have been higher cerebrospinal levels in parkinsonian patients than age-matched controls. Thus, there is a hypotheses to influence the pathogenesis of PD, that is, the excess enzyme activity to activate neurotoxins, such as N-methyltransferase, might be higher in PDs. Indeed, simple betaCs, via N-methylation steps, induced bradykinesia with the decreased dopamine contents in the striatum and midbrain in C57/BL mice. In younger (65 years old) PD patients, the excretion amount of N(1)-methyl-nicotinamaide was significantly higher than that in younger controls. The protein amount of nicotinamide N-methyltransferase (NNMT) was also significantly higher in younger PD patients than that in younger controls. These findings described here would indicate that the excess N-methylation ability for azaheterocyclic amines, such as betaCs, before the onset had been implicated in PD pathogenesis. On the other hand, the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
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PMID:N-methylation underlying Parkinson's disease. 1220 Jan 90

Multiple chemical sensitivity (MCS) is a condition where previous exposure to hydrophobic organic solvents or pesticides appears to render people hypersensitive to a wide range of chemicals, including organic solvents. The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide-mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite-mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite-mediated increased permeability of the blood-brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis-driven MCS research.
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PMID:NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity. 1220 32

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

Bromocriptine, a dopamine D2 receptor agonist, is widely used for treating prolactinoma, Parkinson's disease and galactorrhea. However, the influence of bromocriptine on the endocrine system, especially adrenal function, is not clear. The present study was aimed to investigate the effects of bromocriptine on corticosterone production in rats. Male rats were treated or not treated by bromocriptine (5 mg/kg, s.c.) twice per day for 2 days before decapitation. The adrenal zona fasciculata-reticularis cells were prepared and incubated with adrenocorticotropic hormone (ACTH), forskolin (an adenylyl cyclase activator), 8-bromo-adenosine 3':5' cyclic monophosphate (8-Br-cAMP, a membrane-permeable analogue of cAMP), and steroidogenic precursors including 25-OH-cholesterol and pregnenolone. The concentrations of prolactin, corticosterone and pregnenolone in the plasma and/or medium were measured by radioimmunoassay (RIA). The protein expression of cytochrome P450 side-chain cleavage (P450scc) enzyme and steroidogenic acute regulatory protein (StAR) was analyzed by Western blotting. Administration of bromocriptine in vivo resulted in a decrease in the levels of plasma prolactin and corticosterone. Basal--and ACTH--as well as forskolin-stimulated corticosterone secretion by zona fasciculata-reticularis cells was also lower in bromocriptine-treated rats than in control animals. The decreased production of corticosterone in zona fasciculata-reticularis cells could be reversed by administration of 8-Br-cAMP. The corticosterone and pregnenolone release induced by 25-OH-cholesterol in zona fasciculata-reticularis cells was reduced by administration of bromocriptine. The protein expression of both StAR protein and P450scc in zona fasciculata-reticularis cells was inhibited in the bromocriptine-treated group. Administration of bromocriptine in vitro reduced the release of corticosterone stimulated by ACTH and forskolin in rat zona fasciculata-reticularis cells. These results suggested that bromocriptine caused adrenal dysfunction through inhibition of ACTH action and of the activity of adenylyl cyclase, and impaired the early steps of corticosterone biosynthesis.
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PMID:Inhibitory effects of bromocriptine on corticosterone secretion in male rats. 1274 21

Increasingly, atypical antipsychotic drugs are prescribed for elderly patients with symptoms of psychosis and behavioral disturbances. These symptoms often occur in patients with Alzheimer's disease, other dementias, or Parkinson's disease. As the average age of Americans increases, the prevalence of Alzheimer's disease and Parkinson's disease will rise accordingly. Although nonpharmacologic treatments for behavioral disturbances should be tried first, medications often are needed to enable the patient to be adequately cared for. Current guidelines recommend using risperidone and olanzapine to treat psychosis in patients with Alzheimer's dementia. Quetiapine and clozapine are recommended for treatment of psychosis in patients with Parkinson's disease. Additional research is needed for a recently approved agent, ziprasidone. To minimize side effects, these medications should be started at low dosages that are increased incrementally. Drug interactions, especially those involving the cytochrome P450 system, must be considered. Clozapine's potentially lethal side effects limit its use in the primary care setting. Informed use of atypical antipsychotic drugs allows family physicians to greatly improve quality of life in elderly patients with dementia and behavior disturbances.
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PMID:Use of atypical antipsychotic drugs in patients with dementia. 1531 32

The aim of the present investigation was to characterize the cytochrome P450 (CYP)-dependent metabolism of l-deprenyl by brain microsomal preparations obtained from two different animal models that have been extensively used in Parkinson's disease studies, namely monkey (Cercopithecus aethiops) and C57BL/6 mouse. In monkey brain microsomal fractions, the apparent Km values for methamphetamine formation from l-deprenyl were 67.8 +/- 1.0 and 72.0 +/- 1.6 microm, in the cortex and striatum, respectively. Similarly, for nordeprenyl formation from l-deprenyl, Km values in cortex and striatum were 21.3 +/- 3.2 and 27.3 +/- 4.0 microm, respectively. Both metabolic pathways appear to be more efficient in the cortex than in the striatum as the Vmax for microsomal preparation was lower in the striatum for the formation of both metabolites. The formation rate of l-methamphetamine was up to one order of magnitude greater than that of nordeprenyl. Inhibition analysis of both pathways in monkey brain suggested that l-methamphetamine formation is catalysed by CYP2A and CYP3A, whereas only CYP3A appears to be involved in nordeprenyl formation. With microsomal preparations from whole brain of C57BL/6 mice, the only l-deprenyl metabolite that could be detected was methamphetamine and the Km and Vmax values were similar to those determined in monkey cortex (53.6 +/- 2.9 microm and 33.9 +/- 0.4 pmol/min/mg protein, respectively). 4-Methylpyrazole selectively inhibited methamphetamine formation, suggesting the involvement of CYP2E1. In conclusion, the present study indicates that l-deprenyl is effectively metabolised by CYP-dependent oxidases in the brain, giving rise mainly to the formation of methamphetamine, which has been suggested to play a role in the pharmacological effects of the parent drug. The results also demonstrate that there are differences between species in CYP-dependent metabolism of l-deprenyl.
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PMID:Cytochrome P450-dependent metabolism of l-deprenyl in monkey (Cercopithecus aethiops) and C57BL/6 mouse brain microsomal preparations. 1291 25

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a dopaminergic toxin which produces Parkinson's disease-like symptoms in primates and dopaminergic cell loss in mice. MPTP is bioactivated through monoamine oxidase to MPP(+) and detoxified by cytochrome P450 to nor-MPTP. We have examined metabolisms of MPTP to nor-MPTP by mouse brain microsomes and compared it with corresponding activity in liver. In brain, but not in liver, this biotransformation was completely abolished by quinidine, an inhibitor of P4502D. Northern blotting experiments demonstrated constitutive expression of cytochrome P4502D mRNA predominantly in neuronal cells within the cortex, hippocampus, thalamus, Purkinje and granule cell layers of the cerebellum and in the reticular neurons of midbrain. Striatal neurons were sparsely stained indicating a relative paucity of expression. These studies demonstrate for the first time that detoxification of MPTP to nor-MPTP occurs in mouse brain through cytochrome P4502D which is primarily localized in neuronal cells. Cytochrome P4502D6 is known to exhibit genetic polymorphism in humans, and a defect in this isoform could potentially lead to decreased detoxification of neurotoxins in certain neuronal sub-population, which in turn may have implications in pathogenesis of Parkinson's disease.
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PMID:Characterization and localization of cytochrome P450 mediated metabolism of MPTP to nor-MPTP in mouse brain: relevance to Parkinson's disease. 1471 67

Experimental Parkinson's disease and Parkinson's disease in humans include a CNS inflammatory component that may contribute to the pathogenesis of the disease. CNS inflammation produces a loss in cytochrome P450 metabolism and may impair the brain's protection against neurotoxins. We have examined if preexisting inflammation in the brain could increase the toxicity of the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP(+)). Lipopolysaccharide (LPS, 25 microg) or saline (control) was injected into the left lateral cerebral ventricle. A single injection of MPP(+) into the median forebrain bundle followed 48 h later and produced a reduction in striatal dopamine content that was dose- and time-dependent. Two-days after 5 microg of MPP(+) was administered, a 90% decrease in striatal dopamine content was observed in saline- and LPS-pretreated rats. However, 4 and 7 days after 5 microg MPP(+) treatment, striatal dopamine recovered up to 70-80% of control values in saline-pretreated rats but remained depressed (80-90%) in rats treated with LPS. These results suggested that CNS inflammation might create an increased risk factor for drug-induced CNS toxicity or chemically mediated Parkinson's disease. The prolonged toxicity of MPP(+) may be due to a decrease in brain cytochrome P450 metabolism that occurs during inflammation. As a second objective for the study, we examined if the CNS lesion produced by MPP(+) altered cytochrome P450 metabolic activity in the liver, kidney, and lung. We have demonstrated a novel mechanism whereby the brain pathology produced by MPP(+) treatment contributes to a reduction in cytochrome P450 metabolism in the kidney but not the liver or lung. Therefore, a chemically evoked CNS disorder with a chronic inflammatory component might have major effects on the renal metabolism of drugs or endogenous substrates.
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PMID:Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats. 1509 8

Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease.
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PMID:Cytochrome P450 in neurological disease. 1518 Apr 92

Elucidation of the biochemical steps leading to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal dopamine (DA) pathway has provided new clues to the pathophysiology of Parkinson's disease. In line with the enhancement of MPTP toxicity by diethyldithiocarbamate (DDC), here we demonstrate how other cytochrome P450 (CYP) 2E1 inhibitors, such as diallyl sulphide (DAS) and phenylethylisothiocyanate (PIC), also potentiate the selective DA neurone degeneration in C57/bl mice. In addition, we show that CYP 2E1 is present in the brain and in the basal ganglia of this mouse strain, as measured by RT-PCR, western blot analysis and immunohistochemistry. A kinetic analysis of MPTP and its metabolites, by means of the microdialysis technique in the striatum, indicates that no detoxification metabolic pathway is affected by any of these inhibitors. This does not rule out, however, that an undetected detoxification pathway involving CYP 2E1 is operating. In order to provide direct evidence for this isozyme involvement, CYP 2E1 knockout mice were challenged with MPTP or the combined treatment. Here we show that these transgenic mice have a low sensitivity to MPTP alone, similar to their wild-type counterparts, suggesting that it is likely that transgenic mice compensate for the missing enzyme. However, DDC pretreatment completely fails to enhance MPTP toxicity in CYP 2E1 knockout mice, whereas this enhancement is regularly present in wild-type animals. This study indicates that the occurrence of CYP 2E1 in C57/bl mouse brain is relevant to MPTP toxicity, and suggests that this isozyme may have a detoxificant role related to the efflux transporter of the toxin.
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PMID:Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. 1544 62


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