DOXORUBICIN-INDUCED DISTURBANCE OF THE ENERGY-METABOLISM AFTER HEPATECTOMY

This study was designed to clarify effects of gamma-glutamylcysteine e thyl ester, a prodrug of glutathione, on doxorubicin-induced changes i n liver energy metabolism after hepatectomy. Rats were divided into tw o major groups dependent on whether hepatectomy had been performed. Ra ts undergoing hepatectomy were subdivided into three groups: the contr ol group, 70% of the liver was resected; the doxorubicin group, after hepatectomy 2 mg/kg body weight doxorubicin was administered intraperi toneally; and the doxorubicin + gamma-glutamylcysteine group, 30 min b efore hepatectomy 50 mg/kg body weight of gamma-glutamylcysteine ethyl ester was injected intravenously and other procedures were performed as in the doxorubicin group. In the group not undergoing hepatectomy, 2 mg/kg body weight doxorubicin was administered intraperitoneally aft er a sham operation. Rats in each group were sacrificed 24, 72, and 12 0 hr after hepatectomy or sham operation, and the remnant liver was is olated. Liver mitochondrial function, adenine nucleotide concentration s, and glutathione and glutathione peroxidase activities were determin ed. Doxorubicin did not show any significant effects on parameters mea sured in rats not undergoing hepatectomy. Liver mitochondrial function was increased significantly 24 hr after hepatectomy, and significant decreases in adenine nucleotide concentrations were observed 24 and 72 hr after hepatectomy. Doxorubicin inhibited the increase in mitochond rial function associated with hepatectomy and delayed recovery of live r adenine nucleotide concentrations. Significant increases in tissue g lutathione concentrations were observed 24 and 72 hr after hepatectomy . These significant increases in glutathione concentrations were not o bserved in rats treated with doxorubicin 72 hr after hepatectomy. Furt hermore, doxorubicin decreased glutathione peroxidase activity after h epatectomy. Administration of gamma-glutamylcysteine ethyl ester lesse ned these doxorubicin-induced changes. These results indicate that cha nges in the glutathione redox system might be involved in the doxorubi cin-induced deterioration of the remnant Liver energy metabolism. Clin ical application of gamma-glutamylcysteine ethyl ester might be expect ed. (C) 1996 Academic Press, Inc.