Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thioredoxin reductase (TR) is a widely distributed flavoenzyme that provides reduced thioredoxin, a dithiol hydrogen donor for protein disulfide reduction and for the reduction of ribonucleotides to deoxyribonucleotides, the first unique step of DNA synthesis. Antitumor quinones were found to exhibit time- and concentration-dependent inhibition of purified rat liver TR that requires the presence of NADPH. Diaziquone initially shows competitive inhibition of the enzyme with 5,5'-dithiobis 2-nitrobenzoic acid as substrate with a Ki of 7.5 microM, which becomes non-competitive after 1 hour incubation with NADPH with a Ki of 0.5 microM. Doxorubicin shows non-competitive inhibition both initially and after 1 hr incubation with NADPH, with Ki values of 10 microM and 0.5 microM, respectively. Electron spin resonance spectroscopy showed the formation of semiquinone free radicals by TR incubated under anaerobic conditions with doxorubicin or diaziquone and NADPH. Redox cycling and formation of oxygen radicals does not play a major role in the inhibition of TR by antitumor quinones as shown by the minor effect on inhibition of removing O2, and the lack of effect of superoxide dismutase and catalase. Diaziquone causes time- and concentration-dependent inhibition of TR activity in intact A204 human rhabdomyosarcoma cells that is associated with growth inhibition. The results suggest that inhibition of TR by antitumor quinones could contribute to their growth inhibitory properties.
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PMID:Inhibition of thioredoxin reductase (E.C. 1.6.4.5.) by antitumor quinones. 216 13

Doxorubicin and mitoxantrone were given to mice in a single dose of 15 mg/kg body wt (i.p.) and lipid peroxidation assays were carried out 3, 4 and 5 days after injection. Four days after injection, mitoxantrone induced an increase of 155% in liver spontaneous chemiluminescence and increases of 73% and 52% in malonaldehyde levels and hydroperoxide-initiated chemiluminescence of liver homogenates. Three days after injection, administration of doxorubicin produced increases of 51% and 53% in liver spontaneous chemiluminescence and malonaldehyde formation respectively, but no changes in hydroperoxide-initiated chemiluminescence of liver homogenates were observed. The hepatic levels of antioxidant enzymes were measured in mice treated with doxorubicin or mitoxantrone. Administration of mitoxantrone caused decreases of 50%, 27% and 42% in Cu-Zn superoxide dismutase, catalase and glutathione peroxidase activities, respectively. Doxorubicin also induced decreases in antioxidant enzyme levels but the effect was less marked. Our studies suggest that mitoxantrone might be more hepatotoxic than doxorubicin and that the mechanism of its toxicity would involve a reduction in antioxidant defenses.
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PMID:Hepatotoxicity of mitoxantrone and doxorubicin. 239 34

The purpose of this study was to correlate the exercise-induced changes of oxidant stress enzymes with possible modification of the response to the putative oxidant stressor doxorubicin. Enzymatic and histological changes were studied in mice placed on a 21-wk swim training program (1 h/day, 5 days/wk) with and without anthracycline administration. Doxorubicin (4 mg/kg) was administered intravenously through a tail vein on 10 separate days over a 7-wk period (twice weekly during weeks 10, 11, 14, 15, and 16). Blood, liver, and heart levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GP) were measured following the 9th and 21st wk. Myocardial histomorphological observations were made by light microscopy after 21 wk. Following 9 wk of training swim-trained animals had significantly elevated levels of CAT, SOD, and GP in blood, as well as elevated GP in liver. After 21 wk, trained animals, regardless of drug status, had elevated blood CAT and SOD activity and increased liver CAT and GP. Training also produced increases in blood GP, liver SOD, and heart CAT; however, in conjunction with doxorubicin these changes were not seen. The degree of cardiotoxicity was significantly greater in the sedentary drug-treated animals than in the swim-trained drug-treated animals. The results suggest a correlation between antioxidant enzyme levels in blood and liver and the degree of damage caused by an anthracycline drug. It was concluded that exercise ameliorates severe toxic damage caused by doxorubicin administration, possibly by increasing enzymes that combat free radical damage.
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PMID:Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin. 405 7

We have investigated the effect of doxorubicin (Adriamycin) on the yeast Saccharomyces cerevisiae. Drug treatment was found to be cytotoxic to wild-type strains, in a concentration-dependent manner, whereas a petite mutant lacking the cytochrome oxidase (EC 1.9.3.1) subunit IV gene was resistant to doxorubicin. Transformation of the doxorubicin-resistant mutant with a yeast in vivo expression vector harboring the cytochrome oxidase subunit IV gene restored both respiration and sensitivity to doxorubicin. Another petite strain, with a mutation in the mitochondrial adenine nucleotide translocator (pet9), did not display doxorubicin resistance. However, in contrast to the subunit IV mutant, it possesses a functional respiratory chain. We also compared the cytotoxic effect of doxorubicin with those of daunorubicin and mitoxantrone in yeast. We found comparable levels of cytotoxicity for doxorubicin and daunorubicin, which were significantly greater than that for mitoxantrone. Finally, we constructed a yeast strain that overexpresses manganese superoxide dismutase (EC 1.15.1.1), an antioxidant enzyme present in mitochondria. Overexpression of manganese superoxide dismutase protected significantly against doxorubicin and daunorubicin cytotoxicity but only slightly against mitoxantrone cytotoxicity. Collectively, our results provide direct in vivo evidence that superoxide radicals participate in doxorubicin- and daunorubicin-induced cytotoxicity in yeast. Furthermore, these results indicate that mitochondrial respiration is a crucial factor in anthracycline, and perhaps mitoxantrone, cytotoxicity in yeast.
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PMID:Doxorubicin, daunorubicin, and mitoxantrone cytotoxicity in yeast. 780 47

The effect of Adriamycin (ADM) administration on heart mitochondria was investigated in rats at rest and after an acute bout of maximal exercise. ADM was given intravenously at a dosage of 8 mg/kg body weight 24 and 1 hr before rats were decapitated. Respiratory functions of the isolated heart mitochondria were measured polarographically with both site 1 (pyruvate-malate and 2-oxoglutarate) and site 2 (succinate) substrates. State 4 (basal) respiration was increased using all substrates in ADM-treated rat hearts compared with non-drug control hearts. The mitochondrial respiratory control index was decreased with ADM, but the reduction was due to an increase in state 4 rather than a decrease of state 3 (ADP-stimulated) respiration. ADM administration abolished an exercise-induced elevation of state 3 respiration using all substrates. There was no significant myocardial oxidative damage of dysfunction as evaluated by lipid peroxidation and antioxidant enzyme activity. Addition of exogenous free radicals to the respiratory medium using hypoxanthine and xanthine oxidase resulted in significant deterioration of mitochondrial function in all parameters measured, but no drug- or exercise-specific patterns of damage were revealed. It is concluded that the current dose of ADM (20% of the established cumulative toxic dose) administered within 24 hr can interfere with normal heart mitochondrial function both at rest and during heavy exercise, but does not elicit overwhelming oxidative damage to the myocardium.
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PMID:Effects of Adriamycin on heart mitochondrial function in rested and exercised rats. 813 63

Cross-resistance presents an obstacle in cancer chemotherapy. Cadmium is a potential carcinogen whose exposure has been shown in epidemiological and laboratory experiments to cause lung cancer. Cadmium also induces various forms of resistance in human lung carcinoma cells. This resistance may be shared by antineoplastic agents, which should be a concern for chemotherapy of cadmium-induced lung cancer. In the present study, two subpopulations of human lung carcinoma A549 cells with a different magnitude of resistance to cadmium toxicity were shown to have a parallel resistance to the cytotoxic action of Adriamycin (ADR), an important anticancer drug. Several factors were examined to investigate the mechanism(s) for the cross-resistance, including cellular metallothionein and glutathione (GSH) concentrations, glutathione S-transferase activity, mdr1 expression, and antioxidant enzyme activities including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Only cellular GSH content was elevated consistently in the cadmium/ADR-resistant cells relative to the cadmium/ADR-sensitive cells. Treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis sensitized both cell lines to ADR only when the cellular GSH levels were depleted to about 5% of control. This BSO treatment, however, did not affect cell viability. Further study revealed that the cadmium/ADR-resistant cells have a greater capacity in recovery of cellular GSH content following BSO treatment. The results demonstrate that cross-resistance to ADR exists in cadmium-resistant human lung carcinoma A549 cells, and enhanced GSH synthesis capacity, rather than elevated levels of cellular GSH, may be related to this resistance.
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PMID:Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells. 911 95

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)2D3 and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)2D3 resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)2D3 (10 nM) followed by a 24-h treatment with 1 microg/ml doxorubicin was 74+/-9% (mean +/- SE). Under these experimental conditions, 1,25(OH)2D3 on its own did not affect cell number or viability. 1,25(OH)2D3 also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)2D3 and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin. 1,25(OH)2D3 also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)2D3 alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)2D3 and doxorubicin and may also suggest increased efficacy of 1,25(OH)2D3 or its analogues in combination with other ROS-generating anticancer therapeutic modalities.
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PMID:1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. 1002 76

Doxorubicin continues to be one of the most widely used anticancer agents in the clinic despite its dose-limiting side-effects. Many of doxorubicin's dose-limiting toxicities occur due to its generation of toxic oxygen species, resulting in oxidative stress. Some clinical observations have suggested that doxorubicin may have greater toxicity in older patients. The studies presented here compare basal and doxorubicin-induced antioxidant enzyme activities in brain, heart, kidney and liver tissues of Fisher 344 rats of different ages to determine whether differences in these enzymes can account for the age-dependent differences observed in doxorubicin-induced toxicity. Three groups of animals were tested, young animals (2-months-old), adult animals (10-months-old) and old animals (18-months-old). The results of these studies show that in general young and adult animals have similar levels of antioxidant enzyme activity while the older animals have less. Only in the young animals is antioxidant enzyme activity significantly increased following doxorubicin treatment suggesting that enzyme induction occurs only in the young group of animals. Lipid peroxidation is shown to have the greatest increase in the old animals following doxorubicin treatment while the young animals have the smallest increase. The results from these studies suggest that there is an increase in doxorubicin-induced oxidative damage with age and that these differences may be due to basal and drug-induced differences in tissue antioxidant enzyme activities.
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PMID:Basal and drug-induced antioxidant enzyme activities correlate with age-dependent doxorubicin oxidative toxicity. 1090 15

The cytostatic Adriamycin and the herbicide paraquat form reactive oxygen species during enzymatic activation. Adriamycin, but not paraquat, is also able to intercalate into DNA and to interfere with DNA synthesis and transcription. We investigated the influence of both substances on antioxidant enzyme expression in primary rat hepatocytes. Treatment of hepatocytes with Adriamycin led to an increase in catalase and a decrease in MnSOD mRNA expression. In contrast, exposure of hepatocytes to paraquat resulted in an increase in both catalase and MnSOD message levels. CuZnSOD mRNA was not responsive to either treatment. Adriamycin almost completely inhibited RNA synthesis, but paraquat did not change either RNA or protein synthesis. Both substances induced lipid peroxidation as measured by the accumulation of malondialdehyde in the medium. These findings indicate that catalase and MnSOD are not regulated coordinately in hepatocytes and that ROS-producing agents can differentially influence expression of antioxidant enzymes depending on their capacity to inhibit transcription.
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PMID:Influence of Adriamycin and paraquat on antioxidant enzyme expression in primary rat hepatocytes. 1095 98

Excessive generation of reactive oxygen intermediates can induce changes in the cellular antioxidant defence system. In this study we examine the antioxidant enzyme status and the expression of fibrosis-related marker proteins in the Adriamycin model of chronic renal failure in the rat. Twenty weeks after Adriamycin treatment, rats have overt nephrotic syndrome and renal failure with development of tubulo-interstitial fibrosis and glomerulosclerosis. Lipids accumulate in blood and in both glomeruli and tubulo-interstitial tissue. Desmin and alpha-smooth muscle actin expression increases in glomeruli and in the tubulo-interstitial area. Renal cortex antioxidant enzyme activities are decreased 20 weeks after Adriamycin injection (to 41% for catalase, to 56% for total superoxide dismutase and to 69% for glutathione peroxidase). The mRNA levels of catalase, Cu/Zn-superoxide dismutase and glutathione peroxidase-1 evaluated by Northern blot are decreased by more than 50% for catalase, Cu/Zn-superoxide dismutase and glutathione peroxidase-1. We conclude that in the rat Adriamycin-induced model of chronic renal failure with fibrosis, the combination of decreased antioxidant enzyme status in renal cortex with high concentrations of lipids in blood and renal tissue facilitates oxidative damage. Development of fibrosis is paralleled by increased expression of desmin and alpha-smooth muscle actin.
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PMID:Renal antioxidant enzymes and fibrosis-related markers in the rat adriamycin model. 1101 87


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