Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the effect of oxidative stress on expression of extracellular superoxide dismutase (EC-SOD), CuZn-SOD and Mn-SOD, two fibroblast lines were exposed for periods of up to 4 days to a wide concentration range of oxidizing agents: xanthine oxidase plus hypoxanthine, paraquat, pyrogallol, alpha-naphthoflavone, hydroquinone, catechol, Fe2+ ions, Cu2+ ions, buthionine sulphoximine, diethylmaleate, t-butyl hydroperoxide, cumene hydroperoxide, selenite, citiolone and high oxygen partial pressure. The cell lines were cultured both under serum starvation and at a serum concentration that permitted growth. Under no condition was there any evidence of EC-SOD induction. Instead, the agents uniformly, dose-dependently and continuously reduced EC-SOD expression. We interpret the effect to be due to toxicity. Enhancement of the protection against oxidative stress by addition of CuZn-SOD, catalase and low concentrations of selenite did not influence the expression of any of the SOD isoenzymes. Removal of EC-SOD from cell surfaces by heparin also did not influence SOD expression. Mn-SOD was moderately induced by high doses of the first 11 oxidants. Apart from reduction at high toxic doses, there were no significant effects on the CuZn-SOD activity by any of the treatments. Thus EC-SOD, previously shown to be profoundly influenced by inflammatory cytokines, was not induced by its substrate or other oxidants. In a similar fashion, Mn-SOD, previously shown to be greatly induced and depressed by cytokines, was only moderately influenced by oxidants. We suggest that the regulation of these SOD isoenzymes in mammalian tissues primarily occurs in a manner co-ordinated by cytokines, rather than as a response of individual cells to oxidants.
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PMID:Effects of oxidative stress on expression of extracellular superoxide dismutase, CuZn-superoxide dismutase and Mn-superoxide dismutase in human dermal fibroblasts. 813 41

Cu/Zn-superoxide dismutase (Cu/Zn-SOD) has been shown to modulate the autoxidation of a variety of phenoic compounds, including 1,4-hydroquinone (HQ), a benzene-derived metabolite. The acceleration of autoxidation of HQ by Cu/Zn-SOD results in the production of 1,4-benzoquinone (BQ). It has been proposed that the chemical mechanism involved in the Cu/Zn-SOD-catalyzed autoxidation of HQ may be occur through either its conventional activity as a superoxide:superoxide oxidoreductase or as a semiquinone:superoxide oxidoreductase. However, Cu/Zn-SOD-accelerated oxidation of HQ has not been resolved experimentally. In this study, with ESR spectroscopy we investigated further the chemical reactions involved in the SOD-accelerated oxidation of HQ. In phosphate-buffered saline (PSB), HQ underwent a slow autoxidation to BQ, which was accelerated by Cu/Zn-SOD, Mn-SOD, or Fe-SOD with similar efficiency. In contrast, among free metals, only Cu(II) strongly mediated the oxidation of HQ to BQ. Mn(II) exhibited a slight capacity to oxidize HQ, whereas neither FE(II) nor FE(III) was capable of modulating the autoxidation of HG. The presence of either form of SOD also dramatically enhanced the formation of semiquinone anion radicals SQ-. from HQ. The SOD-accelerated oxidation of HQ was also accompanied by the generation of H202. In PBS containing bovine serum albumin (BSA) (PBS/BSA), HQ did not undergo autoxidation to SQ-., and as such the presence of SOD was unable to induce the formation of either SQ-. or BQ or the consumption of O2. The addition of 10 microM BQ to HQ (100 or 1000 microM) in PBS/BSA resulted in the formation of SQ-. and initiated a slow rate of oxidation of HQ to BQ. In this case, the presence of Cu/Zn-SOD strongly accelerated the oxidation of HQ to SQ-. and BQ and the utilization of O2. Furthermore, the enhancement by Cu/Zn-SOD of the generation of SQ-. or BQ from HQ in PBS/BSA was extensively inhibited under anaerobic conditions. The enhancement of SQ-. generation from HQ by all three forms of SOD does not support the possibility that Cu/Zn-SOD can oxidize SQ-. to BQ. Taken together, this study demonstrates that unlike free copper, Cu/Zn-SOD does not directly interact with HQ to cause its oxidation to BQ. Rather, the autoxidation of HQ to SQ-. is a prerequisite for the enhancing capacity of Cu/Zn-SOD, and the dismutation of superoxide anion radicals generated from the SQ-. in the presence of O2 appears to be the underlying mechanism responsible for the enhancement by Cu/Zn-SOD of the oxidation of HQ.
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PMID:Role of Cu/Zn-superoxide dismutase in xenobiotic activation. I. Chemical reactions involved in the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone. 864 79

Cu/Zn-superoxide dismutase (SOD)-accelerated oxidation of the benzene metabolite 1,4-hydroquinone (HQ) results in the enhanced formation of semiquinone anion radicals, electrophilic 1,4-benzoquinone (BQ), and H202. We selected bone marrow stromal cells and phiX-174 double stranded plasmid DNA as model systems to investigate the cytotoxicity and DNA cleaving activity of the Cu/Zn-SOD-mediated activation of HQ. The addition of either Cu/Zn-SOD or Min-SOD to the primary bone marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity, which could be completely prevented by adding reduced glutathione (GSH) or dithiothreitol but not be adding catalase. Incubation of the plasmid DNA with the HQ/Cu/Zn-SOD system resulted in the induction of single- as well as double-strand breaks, which could be inhibited by catalase and the Cu(I) chelators, bathocuproinedisulfonic acid (BCS) and GSH. Although Mn-SOD could enhance HQ-induced cytotoxicity to stromal cells, the activation of HQ by Mn-SOD did not contribute to the induction of DNA strand breaks. Similar to the HQ/Cu(II) and H202/Cu(II) systems, the DNA strand breaks mediated by HQ/Cu/Zn-SOD could not be effectively inhibited by the hydroxyl radical scavengers, including dimethylsulfoxide, mannitol, and 5,5-dimethyl-1-pyrroline N-oxide, but could be protected by sodium azide. Low-temperature electron spin resonance experiments showed that incubation of Cu/Znu-SOD with HQ resulted in the release of copper from the Cu/Zn-SOD, which could be prevented by catalase. Alpha-(4-Pyridyl-1-oxide)-N-tert-butylnitrone (POBN)/spin-trapping studies demonstrated that the interaction of HQ with Cu/Zn-SOD, but not with Mn-SOD, resulted in the significant formation of POBN-CH3 adduct in the presence of dimethylsulfoxide, suggesting the production of hydroxyl radical or its equivalent from this enzyme/xenobiotic interaction. The formation of the POBN-CH3 adduct from the HQ/Cu/Zn-SOD could be inhibited by catalase, BCS or GSH, indicating the important role for H202 and Cu(I) in the production of reactive oxygen species. Addition of human myeloperoxidase to the HQ/Cu/Zn-SOD synergistically enhanced the formation of BQ from HQ. This enhancement could be abolished by catalase. Taken together, these results demonstrate that activation of HQ by either Cu/Zn-SOD or Mn-SOD results in cytotoxicity to primary bone marrow stromal cells through the formation of electrophilic BQ. Interaction of HQ with Cu/Zn-SOD causes oxidative damage to Cu/Zn-SOD, leading to the release of copper from the enzyme. The further reaction between the released copper and H202 generates reactive oxygen species that participate in the induction of strand breaks in plasmid DNA. The H202 generated from the Cu/Zn-SOD-accelerated oxidation of HQ can also be utilized by myeloperoxidase resulting in additional conversion of HQ to BQ.
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PMID:Role of Cu/Zn-superoxide dismutase in xenobiotic activation. II. Biological effects resulting from the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone. 864 80

To clarify the mechanisms by which hydroquinone (HQ; 1,4-benzenediol) produces apoptosis, HQ-induced cytotoxicity, intemucleosomal DNA fragmentation, activation of superoxide dismutase (SOD), expression of Mn and Cu/ZnSOD mRNA and activation of caspase-3, -8 and -9 were investigated in the human promyelocytic leukemic cell line HL-60. Electrophoresis and activity staining of the SOD-enriched fraction showed that HQ reduced MnSOD activation more than Cu/ZnSOD activation, suggesting that it induces mitochondrial dysfunction at an early stage of apoptosis. Furthermore, the expression of MnSOD mRNA was suppressed to a greater extent than that of Cu/ZnSOD mRNA, implying that HQ causes apoptosis by inhibiting MnSOD induction. Release of cytochrome c and activation of procaspase-3 and -9, but not of procaspase-8, occurred more rapidly (as early as 6 h) in HQ-treated cells, suggesting that HQ activates the intrinsic pathway of apoptosis. Addition of the antioxidant N-acetyl-L-cysteine (NAC) significantly reduced the cytotoxicity of HQ. At a concentration that was cytotoxic to 50% of the cells (approximately 0.05 mM), HQ activated caspase-3; this effect was reduced in the presence of NAC. Interestingly, higher concentrations of HQ (0.1-0.2 mM) caused direct cell death; however, when combined with 5 mM NAC, the activation of caspase-3 was strongly enhanced, suggesting the promotion of apoptosis. The activation of caspase-3 by HQ/NAC combinations suggests that NAC, a precursor of intracellular glutathione synthesis, acts as a co-catalyst during HQ-induced apoptosis.
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PMID:Hydroquinone-induced apoptosis in HL-60 cells. 1581 34

Hydroquinone is a benzene-derived metabolite. To clarify whether the reactive oxygen species (ROS) are involved in hydroquinone-induced cytotoxicity, we constructed transformants of Escherichia coli (E. coli) strains that express mammalian catalase gene derived from catalase mutant mice (Cs(b), Cs(c)) and the wild-type (Cs(a)) using a catalase-deficient E. coli UM255 as a recipient. Specific catalase activities of these tester strains were in order of Cs(a) > Cs(c) > Cs(b) > UM255, and their susceptibility to hydrogen peroxide (H2O2) showed UM255 > Cs(b) > Cs(c) > Cs(a). We found that hydroquinone exposure reduced the survival of catalase-deficient E. coli mutants in a dose-dependent manner significantly, especially in the strains with lower catalase activities. Hydroquinone toxicity was also confirmed using zone of inhibition test, in which UM255 was the most susceptible, showing the largest zone of growth inhibition, followed by Cs(b), Cs(c) and Cs(a). Furthermore, we found that hydroquinone-induced cell damage was inhibited by the pretreatment of catalase, ascorbic acid, dimethyl sulfoxide (DMSO), and ethylenediaminetetraacetic acid (EDTA), and augmented by superoxide dismutase (both CuZnSOD and MnSOD). The present results suggest that H2O2 is probably involved in hydroquinone-induced cytotoxicity in catalase-deficient E. coli mutants and catalase plays an important role in protection of the cells against hydroquinone toxicity.
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PMID:Involvement of oxidative stress in hydroquinone-induced cytotoxicity in catalase-deficient Escherichia coli mutants. 1629 29