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:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N-acetyl-p-benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1). However, CYP2E1 induction appears to be insufficient to explain the claimed magnitude of the interaction. We assessed the role of selective depletion of liver mitochondrial glutathione (GSH) by chronic ethanol. Rats were fed the Lieber-DeCarli diet for 10 days or 6 weeks. APAP toxicity in liver slices (% glutathione-S-transferase alpha released to the medium, GST release) and NAPQI toxicity in isolated liver mitochondria (succinate dehydrogenase inactivation, SDH) from these rats were compared with pair-fed controls. Ethanol induced CYP2E1 in both the 10-day and 6-week groups by approximately 2-fold. APAP toxicity in liver slices was higher in the 6-week ethanol group than the 10-day ethanol group. Partial inhibition of NAPQI formation by CYP2E1 inhibitor diethyldithiocarbamate to that of pair-fed controls abolished APAP toxicity in the 10-day ethanol group only. Ethanol selectively depleted liver mitochondrial GSH only in the 6-week group (by 52%) without altering cytosolic GSH. Significantly greater GSH loss and APAP covalent binding were observed in liver slice mitochondria of the 6-week ethanol group. Isolated mitochondria of the 6-week ethanol group were approximately 50% more susceptible to NAPQI (25-165 micromol/L) induced SDH inactivation. This increased susceptibility was reproduced in pair-fed control mitochondria pretreated with diethylmaleate. In conclusion, 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial GSH.
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PMID:Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver. 1214 40

Hepatotoxicity induced by 1,1-dichloroethylene (DCE) is mediated by cytochrome P450-dependent metabolism to reactive intermediates, including the epoxide. We have tested the hypothesis that mitochondria are a primary target of toxicity by investigating dose- and time-dependent effects of DCE on mitochondrial respiration. Hepatotoxicity, as assessed by serum alanine aminotransferase (ALT) activity, was evaluated. We have also determined the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory perturbations and hepatotoxicity. Liver mitochondria were isolated 2 h after DCE (50, 75, 100, 125, and 150 mg/kg) treatment. Glutamate (complex I)- and succinate (complex II)-supported mitochondrial respiration was assessed by measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption. The corresponding respiratory control ratios (RCRs, state 3/state 4) and ADP:O ratios were then calculated. A DCE dose of 125 mg/kg significantly inhibited glutamate- and succinate-supported state 3 respiration, leading to a significant reduction in corresponding RCRs and ADP:O ratios. In time-dependent studies, state 3 respiration rates and RCRs for glutamate-supported respiration were significantly decreased as early as 20 min after DCE (125 mg/kg) treatment, whereas those for succinate-supported respiration were significantly decreased at 90 min. Additionally, ADP:O ratios for glutamate-supported respiration were significantly decreased starting at 60 min, and those for succinate-supported respiration at 90 min. Alterations in mitochondrial function preceded significant increases in ALT activity, which was first manifested at 2 h. Pretreatment with NAC (1200 mg/kg) abrogated DCE-induced GSH depletion and inhibited disturbances in mitochondrial respiration. Moreover, NAC protected against increased ALT activity, suggesting that the protective effect of NAC is due to increased GSH for conjugation reactions and/or its antioxidant property. These results showed that DCE-mediated mitochondrial dysfunction is an early event that preceded the onset of hepatotoxicity.
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PMID:Mitochondrial dysfunction is an early manifestation of 1,1-dichloroethylene-induced hepatotoxicity in mice. 1249 May 82

The effects of normothermia and delayed hypothermia on the levels of N-acetylaspartate (NAA), reduced glutathione (GSH) and the activities of mitochondrial complex I, II-III, IV and citrate synthase were measured in brain homogenates obtained from anaesthetized neonatal pigs following transient in vivo hypoxia-ischaemia. In the normothermic animals there was a significant decrease in complex I activity and in the levels of GSH and NAA when compared to the controls. Delayed hypothermia preserved NAA and GSH at control levels and enhanced the rate of complex II-III activity. There was correlation (R = 0.79) between GSH and NAA levels when data from all three experimental groups were analyzed. Citrate synthase activity was not significantly different in the three groups, indicating maintenance of mitochondrial integrity. These data suggest that delayed hypothermia affords protection of integrated mitochondrial function in the neonatal brain following transient hypoxia-ischaemia.
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PMID:Delayed hypothermia prevents decreases in N-acetylaspartate and reduced glutathione in the cerebral cortex of the neonatal pig following transient hypoxia-ischaemia. 1251 11

The efficacy of two monothiols, N-acetyl-DL-homocysteine thiolactone (NAHT) and glutathione (GSH) either alone or in combination with two vitamins, vitamin B complex and vitamin E were studied in 7 days methylmercury chloride (MMC; I mg kg) intoxicated male Swiss albino mice. Thirteen groups of animals, each containing 6 animals were used for the study. Three groups of animals were kept as control (treated either with vehicle, normal saline or olive oil). Rest of the ten groups were kept as treatment groups. All the animals were treated subcutaneously for 7 days with MMC and one group was sacrificed on the 8th day. The second group was kept without toxicant for another 7 days and were sacrificed on the 15th day. Two MMC pretoxicated groups were treated either with vitamin B complex (20 mg kg) or vitamin E (60 mg kg) and two other groups were treated with N-acetyl-DL-homocysteine thiolactone (40 mg kg) or glutathione (50 mg kg) for another 7 days. The rest of the four groups were treated with either N-acetyl-DL-homocysteine thiolactone or glutathione in combination with either vitamin B complex or vitamin E. All the animals were sacrificed on the 15th day, brain and spinal cord were dissected and estimated for acid phosphatase, alkaline phosphatase, succinic dehydrogenase and alpha mannosidases. Some of the antidotes showed significant recovery of the enzymes in one tissue while some showed significant recovery in the other tissue depicting the need for treating methylmercury poisoned animals with multi-chelation therapy rather than as a monotherapy.
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PMID:Organelle specific enzyme markers as indicators of methylmercury neurotoxicity and antidotal efficacy in mice. 1257 86

In a previous study, we found that treatment of rat heart mitochondria with H(2)O(2) resulted in a decline and subsequent recovery in the rate of state 3 NADH-linked respiration. These effects were shown to be mediated by reversible alterations in NAD(P)H utilization and in the activities of specific Krebs cycle enzymes alpha-ketoglutarate dehydrogenase (KGDH) and succinate dehydrogenase. The purpose of the current study was to examine potential mechanism(s) by which H(2)O(2) reversibly alters KGDH activity. We report here that inactivation is not simply due to direct interaction of H(2)O(2) with KGDH. In addition, incubation of mitochondria with deferroxamine, an iron chelator, or 1,3-dimethyl-2-thiourea, an oxygen radical scavenger, prior to addition of H(2)O(2) did not alter the rate or extent of inactivation. Thus, inactivation does not appear to involve a more potent oxygen radical formed upon metal-catalyzed oxidation. Inactive KGDH from H(2)O(2)-treated mitochondria was reactivated with dithiothreitol, implicating oxidation of a protein sulfhydryl(s). However, the thioredoxin system had no effect, indicating that enzyme inactivation is not due to the formation of intra- or intermolecular disulfide(s) or a sulfenic acid. Upon incubation of mitochondria with H(2)O(2), reduced GSH levels fell rapidly prior to enzyme inactivation but recovered at the same time as enzyme activity. Importantly, treatment of inactive KGDH with glutaredoxin facilitated the GSH-dependent recovery of KGDH activity. Glutaredoxin is characterized as a specific and efficient catalyst of protein deglutathionylation. Thus, the results of the current study indicate that KGDH activity appears to be modulated through enzymatic glutathionylation and deglutathionylation. These studies demonstrate a novel mechanism by which KGDH activity and mitochondrial function can be modulated by redox status.
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PMID:Reversible inactivation of alpha-ketoglutarate dehydrogenase in response to alterations in the mitochondrial glutathione status. 1268 Jul 78

A decrease in total glutathione, and aberrant mitochondrial bioenergetics have been implicated in the pathogenesis of Parkinson's disease. Our previous work exemplified the importance of glutathione (GSH) in the protection of mesencephalic neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase/complex II. Additionally, reactive oxygen species (ROS) generation was an early, contributing event in malonate toxicity. Protection by ascorbate was found to correlate with a stimulated increase in protein-glutathione mixed disulfide (Pr-SSG) levels. The present study further examined ascorbate-glutathione interactions during mitochondrial impairment. Depletion of GSH in mesencephalic cells with buthionine sulfoximine potentiated both the malonate-induced toxicity and generation of ROS as monitored by dichlorofluorescein diacetate (DCF) fluorescence. Ascorbate completely ameliorated the increase in DCF fluorescence and toxicity in normal and GSH-depleted cultures, suggesting that protection by ascorbate was due in part to upstream removal of free radicals. Ascorbate stimulated Pr-SSG formation during mitochondrial impairment in normal and GSH-depleted cultures to a similar extent when expressed as a proportion of total GSH incorporated into mixed disulfides. Malonate increased the efflux of GSH and GSSG over time in cultures treated for 4, 6 or 8 h. The addition of ascorbate to malonate-treated cells prevented the efflux of GSH, attenuated the efflux of GSSG and regulated the intracellular GSSG/GSH ratio. Maintenance of GSSG/GSH with ascorbate plus malonate was accompanied by a stimulation of Pr-SSG formation. These findings indicate that ascorbate contributes to the maintenance of GSSG/GSH status during oxidative stress through scavenging of radical species, attenuation of GSH efflux and redistribution of GSSG to the formation of mixed disulfides. It is speculated that these events are linked by glutaredoxin, an enzyme shown to contain both dehydroascorbate reductase as well as glutathione thioltransferase activities.
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PMID:Cooperative interaction between ascorbate and glutathione during mitochondrial impairment in mesencephalic cultures. 1295 Apr 57

In this work, the topology of mitochondrial O2(-)(radical) and H2O2 generation and their interplay with matrix GSH in isolated heart mitochondria were examined. We observed that complex I releases O2(-)(radical) into the matrix (where it is converted to H2O2 by Mn-SOD) but not into the intermembrane space. No free radical generation was observed from complex II, but succinate treatment caused H2O2 generation from the matrix through a reverse electron flow to complex I. Complex III was found to release O2(-)(radical) into the matrix and into the intermembrane space. Antimycin, which increases steady-state levels of UQO>- (ubisemiquinone at the Qo site) in complex III, enhanced both H2O2 generation from the matrix and O2(-)(radical) production from the intermembrane space. On the other hand, myxothiazol, which inhibits UQO>- formation, completely inhibited antimycin induced O2(-)(radical) toward the intermembrane space and inhibited H2O2 generation from the matrix by 70%. However, myxothiazol alone enhanced H2O2 production from complex III, suggesting that other components of complex III besides the UQO- can cause O2(-)(radical) generation toward the matrix. As expected, mitochondrial GSH was found to modulate H2O2 production from the matrix but not O2- generation from the intermembrane space. Low levels of GSH depletion (from 0-40%, depending on the rate of H2O2 production) had no effect on H2O2 diffusion from mitochondria. Once this GSH depletion threshold was reached, GSH loss corresponded to a linear increase in H2O2 production by mitochondria. The impact of 50% mitochondrial GSH depletion, as seen in certain pathological conditions in vivo, on H2O2 production by mitochondria depends on the metabolic state of mitochondria, which governs its rate of H2O2 production. The greater the rate of H2O2 generation the greater the effect 50% GSH depletion had on enhancing H2O2 production.
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PMID:Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria. 1457 63

A phenolic antioxidant 3-tert-butyl-4-hydroxyanisole (BHA) is a widely used food additive. BHA had cytotoxicity in human monocytic leukemia U937 cells. BHA at 0.75 mM caused nuclear condensation and fragmentation, structural damage in mitochondria, decrease in mitochondrial transmembrane potential, and internucleosomal DNA cleavage. It induced the activities of caspase-3 and/or -7, -6, -8 and -9, especially high when DEVD-MCA was the substrate (caspase-3 and/or -7). DEVDase activity increased in time- and dose-dependent manner and high activity was observed in lysates of cells treated for 3 h at 0.75 mM. Addition of GSH (reduced glutathione) during the treatment of cells with BHA inhibited the induction of DEVDase activity, and the intracellular GSH level decreased as the concentration of BHA was raised. Intracellular ATP levels decreased in time- and dose-dependent manner when the cells were treated with BHA in the presence or absence of glucose. Enzyme activities involved in the respiratory chain were assayed with the mitochondrial fraction prepared from U937 cells. BHA distinctly inhibited NADH-ubiquinone oxidoreductase (complex I) and cytochrome c oxidase (complex IV) at low concentrations. Succinate-ubiquinone oxidoreductase (complex II) was also inhibited, but to somewhat less extent. Without mitochondrial enzymes, BHA stimulated the ubiquinol-dependent reduction of cytochrome c (complex III), but it might have some detrimental effects on the mitochondrial enzyme reaction of complex III. The inhibition of mitochondrial oxidative phosphorylation might corroborate the mechanistic evidence for apoptosis of leukemia cells by BHA. Cell death induced by BHA is primarily ascribable to apoptosis.
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PMID:Molecular mechanism of cell death induced by the antioxidant tert-butylhydroxyanisole in human monocytic leukemia U937 cells. 1499 91

The whole extract of the fresh berries of Hippophae rhamnoides L. (RH-3), which has been reported to provide protection to whole mice, various tissues, cells and cell organelles against lethal irradiation, was further investigated for its effects on mitochondria isolated from mouse liver. Superoxide anion, reduced (GSH) and oxidized glutathione (GSSG) levels, NADH-ubiquinone oxidoreductase (complex I), NADH-cytochrome c oxidoreductase (complex I/II), succinate-cytochrome c oxidoreductase (complex II/III), mitochondrial membrane potential (MMP), lipid peroxidation (LPx) and protein oxidation (PO) were determined for RH-3-mediated radioprotective manifestation. Pre-irradiation treatment of mice with RH-3 (30 mg kg(-1,) i. p.; single dose; -30 min) significantly inhibited the radiation-induced increase in superoxide anions, GSSG, thiobarbituric acid reactive substances (TBARS), complex I, complex I/III activity and MMP maximally at 4 h (P < 0.05). This treatment inhibited the oxidation of proteins (P < 0.05) at all the time periods studied here. This study suggests that pre-irradiation treatment of mice with RH-3 protects the functional integrity of mitochondria from radiation-induced oxidative stress.
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PMID:Protection of mitochondrial system by Hippophae rhamnoides L. against radiation-induced oxidative damage in mice. 1563 1

The present study was undertaken to investigate whether RP-1 treatment protected mitochondrial system against radiation damage and also to unravel the mechanism associated with this process. Radioprotection of mitochondrial system by Podophyllum hexandrum (RP-1) was investigated to understand its mechanism of action. Levels of superoxide anion (O2-), reduced or oxidized glutathione (GSH or GSSG), thiobarbituric acid reactive substance (TBARS), protein carbonyl (PC), ATP, NADH-ubiquinone oxidoreductase (complex-I), NADH-cytochrome c oxidoreductase (complex I/II), succinate-cytochrome c oxidoreductase (complex II/III) and mitochondrial membrane potential (MMP) were studied in mitochondria isolated from liver of mice belonging to various treatment groups. Whole body y-irradiation (10 Gy) significantly (p < 0.01) increased the formation of O2-, PC, and TBARS, upto 24 h as compared to untreated control. RP-1 treatment (200 mg/kg b.w.) to mice 2 h before irradiation reduced the radiation-induced O2- generation within 4 h and formation of TBARS and PC upto 24 h significantly (p < 0.01). Singularly irradiation or RP-1 treatment significantly (p < 0.01) increased the levels of glutathione within an hour, as compared to untreated control. Pre-irradiation administration of RP-1 enhanced levels of GSH induced increase in complex I (upto 16 h), complex I/III (4 h) complex II/III activity (upto 24 h; p < 0.01) and inhibited the radiation-induced decrease in MMP significantly (24 h; p < 0.01). The present study indicates that RP-1 itself modulates several mitichondrial perameters due to its influence on the biochemical milieu within and outside the cells. However, RP-1 treatment before irradiation modulates radiation induced perturbations such as the increase in electron transport chain enzyme activity, formation of O2-, TBARS and PC to offer radioprotection.
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PMID:Modification of radiation damage to mitochondrial system in vivo by Podophyllum hexandrum: mechanistic aspects. 1564 28


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