Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were undertaken to investigate the principal actions underlying mercury-induced oxidative stress in the kidney. Mitochondria from kidneys of rats treated with HgCl2 (1.5 mg/kg i.p.) demonstrated a 2-fold increase in hydrogen peroxide (H2O2) formation for up to 6 hr following Hg(II) treatment using succinate as the electron transport chain substrate. No increase in H2O2 formation was observed when NAD-linked substrates (malate/glutamate) were used, suggesting that Hg(II) affects H2O2 formation principally at the ubiquinone-cytochrome b region of the mitochondrial respiratory chain in vivo. Together with increased H2O2 formation, mitochondrial glutathione (GSH) content was depleted by more than 50% following Hg(II) treatment, whereas formation of thiobarbiturate reactive substances (TBARS), indicative of mitochondrial lipid peroxidation, was increased by 68%. Studies in vivo revealed a significant concentration-related depolarization of the inner mitochondrial membrane following the addition of Hg(II) to mitochondria isolated from kidneys of untreated rats. This effect was accompanied by significantly increased H2O2 formation, GSH depletion and TBARS formation linked to both NADH dehydrogenase (rotenone-inhibited) and ubiquinone-cytochrome b (antimycin-inhibited) regions of the electron transport chain. Oxidation of pyridine nucleotides (NAD[P]H) was also observed in mitochondria incubated with Hg(II) in vitro. In further studies in vitro, the potential role of Ca2+ in Hg(II)-induced mitochondrial oxidative stress was investigated. Ca2+ alone (30-400 nmol/mg protein) produced no increase in H2O2 and only a slight increase in TBARS formation when incubated with kidney mitochondria isolated from untreated rats. However, Ca2+ significantly increased H2O2 and TBARS formation elicited by Hg(II) at the ubiquinone-cytochrome b region of the mitochondrial electron transport chain, whereas TBARS formation was decreased significantly when the Ca2+ uptake inhibitors, ruthenium red or [ethylenebis(oxyethylenenitrilo)]tetraacetic acid (EGTA), were included with Hg(II) in the reaction mixtures. These findings support the view that Hg(II) causes depolarization of the mitochondrial inner membrane with consequent increased H2O2 formation. These events, coupled with Hg(II)-mediated GSH depletion and pyridine nucleotide oxidation, create an oxidant stress condition characterized by increased susceptibility of mitochondrial membranes to iron-dependent lipid peroxidation (TBARS formation). Since increased H2O2 formation, GSH depletion and lipid peroxidation were also observed in vivo following Hg(II) treatment, these events may underlie oxidative tissue damage caused by mercury compounds. Moreover, Hg(II)-induced alterations in mitochondrial Ca2+ homeostasis may exacerbate Hg(II)-induced oxidative stress in kidney cells.
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PMID:Studies on Hg(II)-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria. 851 85

Inhibition analysis of respiration of Leishmania donovani promastigotes in resting, starved and permeabilized cells in the presence of classical electron transfer complex inhibitors such as rotenone, thenoyltrifluoroacetone and antimycin demonstrated the absence of complex I component of the respiratory chain in this organism. Cyanide failed to completely block the oxygen uptake (residual 25-30%) even at high concentrations. The alternative oxidase inhibitor for Trypanosoma brucei, salicylhydroxamic acid (SHAM) had no effect on respiration while the cytochrome o inhibitor orthohydroxydiphenyl (OHD) could block cyanide-insensitive respiration at low concentrations. Succinate-dependent O2 uptake in permeabilized cells follows the classical pathway. Oxidation of NADH by a membrane-rich fraction produced H2O2 as the end product and was insensitive to respiratory chain inhibitors. The presence of NADH-fumarate reductase was demonstrated in membrane-rich fraction and fumarate could reduce H2O2 production from NADH indicating fumarate to be an endogenous substrate for accepting electrons from NADH. A differential route for NADH oxidation was further confirmed by NADH cytochrome c reductase insensitivity to antimycin. A tentative scheme for electron transfer pathway in this organism is proposed in which a reversal of Krebs cycle enzymes occur producing succinate that can be excreted or oxidized depending upon the energy demands of the cell. Inhibition studies also suggest bifurcations of the respiratory chain that can be of minor importance for the organism.
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PMID:Characterization of the respiratory chain of Leishmania donovani promastigotes. 872 Jan 74

Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease.
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PMID:Oxidative stress and antioxidant therapy in Parkinson's disease. 883 Mar 46

The conversion of adrenaline to aminochromes by the human erythrocyte plasma membranes at pH 9.5 was shown to be a complex reaction that proceeded at least by two distinct phases. The first one, corresponding to the formation of adrenochrome, is catalyzed in the presence of the membranes, suggesting the involvement of an enzyme-mediated process. Active oxygen species were identified as intermediates during this phase. Oxygen radical scavengers (catalase and superoxide dismutase) suggested H2O2 and O2- involvement. Adrenochrome formation was stimulated by NADH indicating the participation of another enzyme (NADH dehydrogenase) which is known to be present in the human erythrocyte plasma membrane. The second phase, corresponding to the disappearance of adrenochrome, is also stimulated by NADH and inhibited in the presence of the membranes. In this reaction, adrenochrome is converted to aminochromes via adrenochrome semiquinone. The formation of radical species is demonstrated by EPR spectroscopy. The results led to the proposal of a mechanism for the formation of adrenochrome and other oxidation products from adrenaline.
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PMID:Conversion of adrenaline to indolic derivatives by the human erythrocyte plasma membrane. 893 91

The rate constants of H2O2 decomposition, interaction of catalase complex I with H2O2, and the effective rate constants of catalase inactivation during enzymatic catalysis (k(in)) were determined by transformation of complete kinetic curves of H2O2 decomposition by catalase in reversed micelles of Aerosol OT (AOT) in octane and aqueous solution. Effects of hydration of micelles and AOT, H2O2, and catalase concentrations in the micellar systems on each of three kinetic constants were investigated. Optimal conditions were found which provide for high operational stability and catalytic activity of catalase in micellar systems versus aqueous solutions. Stability of catalase enhances (decreased k(in)) in the presence of reduced glutathione and ethanol in AOT micelles. In reversed AOT micelles, catalase partially dissociates to subunits because their peroxidase activity was demonstrable in cumene hydroperoxide-dependent oxidation of tetramethylbenzidine. Catalase dissociation to monomers is significantly decreased in mixed micelles composed of AOT, Triton X-45, Triton X-100, or Tween-85 and octanol.
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PMID:[Catalytic properties of catalase in microemulsions of surface-active agents in octane]. 899 90

In vivo administration of either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (MA) produces damage to the dopaminergic nervous system which may be due in part to the generation of reactive oxygen species (ROS). The resistance of superoxide dismutase (SOD) over-expressing transgenic mice to the effects of both MPTP and MA suggests the involvement of superoxide in the resulting neurotoxicity of both compounds. Superoxide can be converted by SOD to hydrogen peroxide, which itself can cause cellular degeneration by reacting with free iron to produce highly reactive hydroxyl radicals resulting in damage to proteins, nucleic acids and membrane phospholipids. Hydrogen peroxide has also been reported to be produced via inhibition of NADH dehydrogenase by MPP + formed during oxidation of MPTP by MAO-B and by dopamine auto-oxidation following MA-induced dopamine release from synaptic vesicles within nerve terminals. To test whether hydrogen peroxide is an important factor in the toxicity of either of these two neurotoxins, we created clonal PC12 lines expressing elevated levels of the hydrogen peroxide-reducing enzyme glutathione peroxidase (GSHPx). Elevation of GSHPx levels in PC12 was found to diminish the rise in ROS levels and lipid peroxidation resulting from MA but not MPTP treatment. Elevated levels of GSHPx also appeared to prevent decreases in transport-mediated dopamine uptake produced via MA administration as well as to attenuate toxin-induced cell loss as measured by either MTT reduction or LDH release. Our data, therefore, suggest that hydrogen peroxide production likely contributes to MA toxicity in dopaminergic neurons.
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PMID:Elevated expression of glutathione peroxidase in PC12 cells results in protection against methamphetamine but not MPTP toxicity. 919 Oct 89

Catalase with molecular weight 230 +/- kD was isolated and purified from methylotrophic yeasts Candida boidinii by ion-exchange chromatography. The kinetic characteristics of yeast and bovine liver catalases were compared in the reaction of H2O2 decomposition using a wide range of H2O2 concentrations (up to 0.12 M) and PH (2-10). First order rates constants (k, sec-1) were determined for both enzymes from semi-logarithmic anamorphoses of kinetic curves of H2O2 utilization. Anamorphoses of complete kinetic curves as a function of 1/ln([H2O2]0/[H2O2]t) versus 1/t were used for calculation of the effective rate constants of catalase inactivation during the reaction (k(in), sec-1) and the rate constants of interaction of catalase complex I with the second molecule of H2O2 (k2, M-1.sec-1). The effects of initial catalase concentrations, H2O2, and pH on k, k2, and k(in) were similar for both enzymes. Catalytic constant, k2, and the efficacy expressed as a ratio kcat/Km were 1.87-, 1.45-, and 1.3-fold, respectively, higher for bovine catalase than that of yeast catalase. Operational stability of yeast catalase is 3.5-fold higher than the stability of bovine catalase and much higher during cyclic decomposition of 50 mM H2O2. Enhanced operational stability and inexpensive source of its preparation open prospects for practical applications of yeast catalase for co-immobilization with superoxide dismutase on non-toxic carriers.
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PMID:Comparative kinetic characterization of catalases from Candida boidinii yeast and bovine liver. 927 76

The molecular basis of the adriamycin (AQ)-dependent development of cardiotoxicity is still far from being clear. In contrast to our incomplete understanding of the organ-specific mechanism mitochondria are unequivocally accepted as the locus where the molecular disorder is triggered. A growing number of reports intimate the establishment of unbalanced oxygen activation through heart mitochondria in the presence of anthraquinones. In fact, in contrast to liver mitochondria, isolated heart mitochondria have been unequivocally shown to shuttle single electrons to AQ, giving rise to O2.- formation by autoxidizing AQ. semiquinones. Earlier we have demonstrated the involvement of the exogenous NADH dehydrogenase in this deleterious electron deviation from the respiratory chain. This enzyme that is associated with complex I of the respiratory chain catalyzes the oxidation of cytosolic NADH. AQ activation through isolated heart mitochondria was reported to require the external addition of NADH, suggesting a flux of reducing equivalents from NADH to AQ in the cytosol. Unlike heart mitochondria, intact liver mitochondria, which are lacking this NADH-related pathway of reducing equivalents from the cytosol to the respiratory chain, cannot be made to activate AQ to semiquinones by NADH or any other substrate of respiration. It appears, therefore, that the exogenous NADH dehydrogenase of heart mitochondria exerts a key function in the myocardial toxicogenesis of anthraquinones via oxygen activation through semireduced AQ. Assessing the toxicological significance of the exogenous NADH dehydrogenase in AQ-related heart injury requires analysis of reaction products and their impact on vital bioenergetic functions, such as energy gain from the oxidation of respiratory substrates. We have applied ESR technique to analyze the identity and possible interactions of radical species emerging from NADH-respiring heart mitochondria in the presence of AQ. The following metabolic steps occur causing depression of energy metabolism in the cardiac tissue. After one-electron transfer to the parent hydrophilic anthraquinone molecule destabilization of the radical formed causes cleavage of the sugar residue. Accumulation of the lipophilic aglycone metabolite in the inner mitochondrial membrane diverts electrons from the regular pathway to electron acceptors out of sequence such as H2O2. HO. radicals are formed and affect the functional integrity of energy-linked respiration. The key and possibly initiating role of the exogenous NADH dehydrogenase of cardiac mitochondria in this reaction pathway provides a rationale to explain the selective cardiotoxic potency of the cytostatic anthraquinone glycosides.
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PMID:Analyses of the molecular mechanism of adriamycin-induced cardiotoxicity. 929 55

We determined the activities of NADH dehydrogenase (ND), succinate dehydrogenase, and cytochrome c oxidase (COX) in 29 skin fibroblast lines established from donors ranging in age from 12 gestational weeks to 94 years. The results of this study demonstrate that all three of the enzyme activities examined are greater in adult-derived fibroblasts than in the fetal cell lines. The ratio of enzyme activities that control electron entry into and exit from the electron transport chain varied directly with lucigenin-detected chemiluminescence (an indicator of .O2- generation) and inversely with H2O2 generation. These results indicate a clear difference in the predominant oxidant species generated during fetal and adult stages of life. We also examined the mRNA abundances of different components of the electron transport chain complexes. We observed higher abundances of mitochondrial encoded mRNAs (COX 1 and ND 4) in cell lines established from adults than in fetal cells. No differences in the mRNA abundances of the nuclear encoded sequences (COX 4 and ND 51) were observed in fetal and postnatal-derived lines. Succinate dehydrogenase mRNA abundance was greater in cell lines established from postnatal donors than in fetal cell lines. No significant differences between cell lines established from young and old adults were detected in any of the parameters examined.
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PMID:Development and age-associated differences in electron transport potential and consequences for oxidant generation. 931 77

Inhibitors of complex III increased the DNA strand scission induced by t-butylhydroperoxide (tB-OOH) and cumene hydroperoxide but did not affect DNA damage induced by H2O2. The hypothesis that these effects are selectively linked to inhibition of the electron transport from cytochrome b to cytochrome c1 is validated by the following observations: (1) two complex III inhibitors, antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide, enhanced the tB-OOH-induced DNA cleavage over the same concentration range as that in which inhibition of oxygen consumption was observed; (2) the complex III inhibitor-mediated enhancement of tB-OOH-induced DNA damage was abolished by the complex I inhibitor rotenone or by glucose omission, and (3) the enhancing effects of antimycin A were not observed in respiration-deficient cells. The mechanism whereby the complex III inhibitors potentiate DNA cleavage promoted by tB-OOH was subsequently investigated with intact as well as permeabilized cells. H2O2, produced at the level of mitochondria via a Ca2+-dependent process, was found to account for the enhancing effects of antimycin A.
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PMID:Mechanism of the antimycin A-mediated enhancement of t-butylhydroperoxide-induced single-strand breakage in DNA. 939 23


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