The selective effect of cystathionine on doxorubicin hepatotoxicity in tumor-bearing mice.
The aim of the present study was to examine the protective effect of cystathionine as a cysteine precursor on doxorubicin toxicity in the liver of Ehrlich ascites tumor (EAT)-bearing mice and in the EAT cells. Both compounds were injected intraperitoneally alone or in combination at the following doses: cystathionine at 10 mg and doxorubicin at 5 mg per kg of body weight. In the liver of EAT-bearing mice, glutathione (GSH), cysteine and sulfane sulfur levels as well as the activities of: glutathione S-transferase, gamma-glutamyl transpeptidase, rhodanese and gamma-cystathionase significantly dropped in comparison with healthy animals. Administration of cystathionine elevated GSH and cysteine levels in the livers of EAT-bearing mice and reduced lipid peroxidation. Furthermore, cystathionine increased gamma-glutamyl transpeptidase activity, thereby activating gamma-glutamyl cycle, responsible for proper glutathione metabolism in the cells. Cystationine did not influence sulfane sulfur level and rhodanese and gamma-cystathionase activity in the livers of EAT-bearing mice. It was next shown that cystathionine administered in combination with doxorubicin protected against the drug toxicity since it elevated thiol level, lowering reactive oxygen species content and suppressing lipid peroxidation. This means that, cystathionine in the liver of EAT-bearing mice can both correct harmful effects of carcinogenesis, and protect the liver from doxorubicin cytotoxicity. In contrast, in EAT cells, cystathionine lowered GSH and cysteine levels and did not alter reactive oxygen species level, lipid peroxidation, and gamma-glutamyl transpeptidase activity. All these data indicate that cystathionine action is selectively beneficial for normal cells because it corrects harmful effects induced by EAT development and protects the organism against doxorubicin cytotoxicity without impairing cytotoxicity of this drug to tumor cells.
Kwiecień
Inga
I
Medical Biochemistry, Collegium Medicum, Jagiellonian University, Kopernika 7, 31-034 Cracow, Poland.
Michalska
Magdalena
M
Włodek
Lidia
L
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002286:Carcinoma, Ehrlich Tumor / Q000150:complications / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000517:prevention & control*; D003540:Cystathionine / Q000494:pharmacology*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007202:Indicators and Reagents; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D007202:Indicators and Reagents; D017382:Reactive Oxygen Species; D003540:Cystathionine; D008315:Malondialdehyde; D004317:Doxorubicin; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D000469:Alkaline Phosphatase; D003542:Cystathionine gamma-Lyase; D005978:Glutathione