Role of phospholipase in the genesis of doxorubicin-induced cardiomyopathy in rats.

The role of phospholipase on the mechanism of doxorubicin-induced cardiomyopathy was investigated in the heart mitochondria of Wistar rats. In the in vivo study, rats were divided into 3 groups: 1, the control group, untreated; 2, the doxorubicin 1-day group, in which doxorubicin (4 mg/kg) was injected s.c. once; and 3, the doxorubicin 4-day group, in which doxorubicin (4 mg/kg) was injected once a day for 4 consecutive days. In each group, the level of lipid peroxides and the phospholipase activity, the phospholipid content, and the enzymic activities in the respiratory chain were measured. The doxorubicin 4-day group showed significant increases of lipid peroxide level and phospholipase activity and an inhibition of mitochondrial respiratory function compared with the control group, while the doxorubicin 1-day group showed no significant difference. In the in vitro study, Experiment 1, intact rat heart mitochondria were incubated with 0.1 unit of phospholipase A2. After the incubation, the enzymic activities of the respiratory chain were disturbed in the same manner as in the in vivo experiment. In Experiment 2, rat heart mitochondria were incubated with ascorbate and ferrous sulfate. The experiment demonstrated the elevation of phospholipase activity associated with lipid peroxidation. These results suggested that the enhanced phospholipase activity caused by lipid peroxidation is responsible for the mechanism of doxorubicin-induced cardiomyopathy.