Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol.
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.


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.
Li
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Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Singal
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PK
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D005979:Glutathione Peroxidase / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D011341:Probucol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
D000924:Anticholesteremic Agents; D000975:Antioxidants; D004317:Doxorubicin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D011341:Probucol