Copper deficient rat heart can compensate for doxorubicin-induced oxidant stress.
The hypothesis that copper (Cu) alters drug metabolizing enzymes and functions as an antioxidant nutrient in doxorubicin cardiotoxicity was tested. Male Sprague-Dawley rats were fed Cu adequate (+Cu; 5 mg Cu/kg of diet), marginally Cu deficient (MCu; 1.2 mg Cu/kg of diet), or severely Cu deficient (-Cu; 0.5 mg Cu/kg of diet) diets for 6 wk. Doxorubicin (1, 2, or 4 mg/kg body wt) or saline were administered intraperitoneally 1 time/wk for 4 wk. Compared to control hearts, Cu,Zn superoxide dismutase activity was decreased by 9% in MCu rats and by 21-40% in -Cu rats. Glutathione peroxidase activity was elevated 5-15% in -Cu rats. Doxorubicin administration increased heart Cu,Zn superoxide dismutase activity in +Cu and -Cu rats 18 h after the last of 4 injections, but not 18 h after 1 injection. There was no synergism between doxorubicin and Cu deficiency on lipid peroxidation, plasma creatine phosphokinase, cardiac hypertrophy, electrocardiographic abnormalities, or morphological changes. Heart glutathione S-transferase activity was decreased by Cu deficiency, and like Cu,Zn superoxide dismutase activity, returned to normal in -Cu rats given doxorubicin. Thus, the Cu deficient rat heart may be able to compensate for doxorubicin-induced oxidant stress by increasing the activity of Cu,Zn superoxide dismutase and glutathione S-transferase.
Fischer
J G
JG
Department of Foods and Nutrition, College of Veterinary Medicine, University of Georgia, Athens 30602.
Tackett
R L
RL
Howerth
E W
EW
Johnson
M A
MA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology; D003300:Copper / Q000172:deficiency*; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004435:Eating / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000097:blood / Q000378:metabolism*
D000975:Antioxidants; D003300:Copper; D004317:Doxorubicin; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D003402:Creatine Kinase; D005978:Glutathione