Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites

Doroshow, James H.; Locker, Gershon Y.; Myers, Charles E.

doi:10.1172/jci109642

Cited by 645 publications

(269 citation statements)

References 32 publications

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“…4 In the present experiments, a decrease in the GSHPx activity, first noticed at 2 hours, continued up to 24 hours. This finding Because there was no difference in the heart and body weights at 1, 2, 4, and 24 hours, these data were pooled and expressed as the meanϮSEM of all animals in the control, ADR (adriamycin), and PROBϩADR (probucolϩadriamycin) groups.…”

Section: Discussionsupporting

confidence: 60%

“…1 However, a dose-dependent cardiotoxicity limits its clinical potential. 1,2 Adriamycin has been shown to cause myocardial antioxidant deficit in different animal species, [3][4][5] and probucol, a lipid-lowering drug and antioxidant, has been found to modulate these changes. 6 However, the molecular basis and early sequence of the changes in myocardial antioxidant enzyme activities due to adriamycin and probucol remain to be understood.…”

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confidence: 99%

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Adriamycin-Induced Early Changes in Myocardial Antioxidant Enzymes and Their Modulation by Probucol

2000

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Background-The clinical usefulness of adriamycin is restricted by the development of congestive heart failure. It has been suggested that probucol, a strong antioxidant, completely prevents adriamycin-induced cardiomyopathy without interfering with its antitumor properties. The present study investigated the effects of adriamycin and probucol on myocardial antioxidant enzyme activities and immunoreactive protein levels in rats. Methods and Results-Activities and protein levels of glutathione peroxidase (GSHPx) were significantly decreased from 2 to 24 hours, and those of manganese superoxide dismutase were decreased at 1 and 2 hours after adriamycin treatment. These changes were prevented by probucol. Catalase activity was increased from 2 to 24 hours after adriamycin treatment, but its protein levels were not significantly changed. Copper zinc superoxide dismutase activity and protein level were not changed at any time. Myocardial lipid peroxidation was found to be significantly higher at all time points, and this change was also prevented by probucol. Treatment with probucol alone increased GSHPx activity at 2 weeks, and in these hearts, lipid peroxidation was lower than the control value. Within 24 hours, there was no mortality in any of the groups. Conclusions-It is suggested that an early and persistent decrease in GSHPx activity and protein may play an important role in the pathogenesis of adriamycin-induced cardiomyopathy, worsening heart failure and mortality. (Circulation.

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

Adriamycin-Induced Early Changes in Myocardial Antioxidant Enzymes and Their Modulation by Probucol

2000

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“…Free radicals cause diverse oxidative damage to critical cellular components and membranes in heart tissues [6,7,17]. Moreover, the heart is very sensitive to oxidative stress owing to its highly oxidative metabolism, and it has a lower level of antioxidant defense systems than the liver [5].…”

Section: Introductionmentioning

confidence: 99%

Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes

et al. 2007

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The effect of Schisandra fructus extract (SFE) on doxorubicin (Dox)-induced cardiotoxicity was investigated in H9c2 cardiomyocytes. Dox, which is an antineoplastic drug known to induce cardiomyopathy possibly through production of reactive oxygen species, induced significant cytotoxicity, intracellular reactive oxygen species (ROS), and lipid peroxidation. SFE treatment significantly increased cell survival up to 25%, inhibited intracellular ROS production in a time-and dosedependent manner, and inhibited lipid peroxidation induced by Dox. In addition, SFE treatment induced expression of cellular glutathione S-transferases (GSTs), which function in the detoxification of xenobiotics, and endogenous toxicants including lipid peoxides. Analyses of 31,100 genes using Affymetrix cDNA microarrays showed that SFE treatment up-regulated expression of genes involved in glutathione metabolism and detoxification [GST theta 1, mu 1, and alpha type 2, heme oxygenase 1 (HO-1), and microsomal epoxide hydrolase (mEH)] and energy metabolism [carnitine palmitoyltransferase-1 (CPT-1), transaldolase, and transketolase]. These data indicated that SFE might increase the resistance to cardiac cell injury by Dox, at least partly, together with altering gene expression, especially induction of phase II detoxification enzymes.

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“…The cardiomyocyte is particularly vulnerable to free radical injury because of properties such as a low antioxidant status (Doroshow et al, 1980;Iarussi et al, 2000). Presently, the cardioprotectant dexrazoxane is the only drug with proven efficacy (Cvetkovic and Scott, 2005).…”

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confidence: 99%

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

et al. 2007

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The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m À2 monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m À2 . Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.

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Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites

Cited by 645 publications

References 32 publications

Adriamycin-Induced Early Changes in Myocardial Antioxidant Enzymes and Their Modulation by Probucol

Adriamycin-Induced Early Changes in Myocardial Antioxidant Enzymes and Their Modulation by Probucol

Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study

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