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.