Early changes in myocardial antioxidant enzymes due to adriamycin and modulation by probucol

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Li, Timao
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The clinical usefulness of adriamycin as an antitumor antibiotic is restricted by the risk of developing congestive heart failure (CHF). Increased oxidative stress by free radical formation and antioxidant deficit appears to play a major role in the development of adriamycin-induced cardiomyopathy and CHF. Probucol, a hypolipidemic drug and a strong antioxidant, has been shown to completely prevent adriamycin-induced cardiomyopathy in rats without interfering with its antitumor effects. We have previously reported that myocardial antioxidant reserve was significantly reduced at the severe heart failure stage subsequent to a chronic adriamycin treatment. As our previous studies were done at the late stage of heart failure after multiple treatments with adriamycin (6 * 2.5 mg/kg), it is not known whether these changes in myocardial antioxidant enzymes preceded the occurrence of heart failure or they are a consequence of heart failure. The current study was undertaken to determine the time course of early changes (1-24 hrs) in activities, mRNA abundance and immunoreactive protein levels of myocardial glutathione peroxidase (GSHPx), manganese superoxide dismutase (MnSOD), copperzinc superoxide dismutase (CuZnSOD) and catalase (CAT) in male prague-Dawley rats treated with: (1) a single dose of adriamycin (2.5 mg/kg); and (2) multiple treatments with adriamycin (6 * 2.5 mg/kg). Another goal of this study was to examine the effects of multiple treatments with probucol (3-12 * 10 mg/kg) on myocardial antioxidant enzyme changes with or without adriamycin. We found the protein content of GSHPx was significantly decreased from 2 to 24 hours after a single injection of adriamycin. However, the enzyme activity of GSHPx was not changed at any time point and its mRNA abundance was significantly depressed only at 2 hours after treatment. Upon multiple treatments, the protein level of GSHPx was reduced from 2 to 24 hours and this change was more sever than that seen after one injection. The enzyme activity of GSHPx was also significantly reduced after multiple treatments. Even three weeks after the completion of treatment, this enzyme activity was significantly lower than the control value. These data clearly show, for the first time, that GSHPx was more sensitive to the multiple treatments of adriamycin than other antioxidant enzymes. (Abstract shortened by UMI.)