Doxorubicin-induced disturbance of the energy metabolism after hepatectomy.
This study was designed to clarify effects of gamma-glutamylcysteine ethyl ester, a prodrug of glutathione, on doxorubicin-induced changes in liver energy metabolism after hepatectomy. Rats were divided into two major groups dependent on whether hepatectomy had been performed. Rats undergoing hepatectomy were subdivided into three groups: the control group, 70% of the liver was resected; the doxorubicin group, after hepatectomy 2 mg/kg body weight doxorubicin was administered intraperitoneally; and the doxorubicin + gamma-glutamylcysteine group, 30 min before 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 after a sham operation. Rats in each group were sacrificed 24, 72, and 120 hr after hepatectomy or sham operation, and the remnant liver was isolated. Liver mitochondrial function, adenine nucleotide concentrations, and glutathione and glutathione peroxidase activities were determined. Doxorubicin did not show any significant effects on parameters measured 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 mitochondrial function associated with hepatectomy and delayed recovery of liver adenine nucleotide concentrations. Significant increases in tissue glutathione concentrations were observed 24 and 72 hr after hepatectomy. These significant increases in glutathione concentrations were not observed in rats treated with doxorubicin 72 hr after hepatectomy. Furthermore, doxorubicin decreased glutathione peroxidase activity after hepatectomy. Administration of gamma-glutamylcysteine ethyl ester lessened these doxorubicin-induced changes. These results indicate that changes in the glutathione redox system might be involved in the doxorubicin-induced deterioration of the remnant liver energy metabolism. Clinical application of gamma-glutamylcysteine ethyl ester might be expected.
Akaza
K
K
Department of Surgery II, Faculty of Medicine, University of Nagoya, Japan.
Nonami
T
T
Kurokawa
T
T
Kobayashi
H
H
Harada
A
A
Nakao
A
A
Sugiyama
S
S
Ozawa
T
T
Takagi
H
H
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D004151:Dipeptides / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects*; D005978:Glutathione / Q000032:analysis; D005979:Glutathione Peroxidase / Q000378:metabolism; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D004151:Dipeptides; C067744:N-gamma-glutamylcysteine ethyl ester; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D005979:Glutathione Peroxidase; D005978:Glutathione