Mechanisms of beneficial effects of probucol in adriamycin cardiomyopathy.
Probucol, a lipid-lowering drug, has been shown to offer protection against adriamycin-induced cardiomyopathy. In order to define the mechanism of this protection, we examined changes in antioxidants and lipid peroxidation in hearts as well as lipids in hearts and plasma from rats treated with either adriamycin or adriamycin and probucol with appropriate controls. Any potential free radical quenching as well as growth inhibitory effects of probucol were also examined using Chinese hamster ovary (CHO) cells in culture. In animal model, adriamycin caused a significant depression in glutathione peroxidase and increased plasma and cardiac lipids as well as lipid peroxidation. Probucol treatment modulated adriamycin-induced cardiomyopathic changes and increased glutathione peroxidase and superoxide dismutase activities. In the presence of adriamycin under hypoxic conditions, formation of adriamycin semiquinone radical was detected by ESR. The cell growth in these cultures was also inhibited by adriamycin in a dose-dependent manner. Probucol had no effect on adriamycin-induced growth inhibition as well as formation of semiquinone radicals. It is proposed that probucol protection against adriamycin cardiomyopathy is mediated by increased antioxidants and lipid-lowering without any effect on free radical production.
Iliskovic
N
N
Department of Physiology and St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Canada.
Hasinoff
B B
BB
Malisza
K L
KL
Li
T
T
Danelisen
I
I
Singal
P K
PK
D000818:Animals; D000903:Antibiotics, Antineoplastic; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000188:drug therapy*; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D004317:Doxorubicin; D004578:Electron Spin Resonance Spectroscopy; D006321:Heart / Q000187:drug effects; D008297:Male; D011341:Probucol / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000903:Antibiotics, Antineoplastic; D000924:Anticholesteremic Agents; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; D004317:Doxorubicin; D002784:Cholesterol; D011341:Probucol