Effect of doxorubicin on glutathione and glutathione-dependent enzymes in cultured rat heart cells.
The effect of doxorubicin (DOX) on heart cell glutathione (GSH)-based enzyme systems was investigated in a rat heart myocyte model. Cellular levels of GSH decreased commensurate with viability following exposure to DOX or to the unrelated alkaloidal cardiotoxin emetine. GSH depletion by L-buthionine sulfoximine (L-BSO) did not alter myocyte viability nor doxorubicin (DOX) dose-response. The nitrosourea carmustine (BCNU), which impairs GSH reductase activity, also did not alter DOX cardiotoxicity. Doxorubicin significantly increased glutathione-S-transferase (GST) activity in a time-dependent fashion. In contrast, selenium-dependent glutathione peroxidase activity was reduced by 50%. These findings demonstrate that lowered GSH or GSH reductase levels do not enhance DOX cardiotoxicity in vitro and suggest that DOX may be a substrate for GST.
Paranka
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Cell Pathways, Inc., Denver, Colorado 80290.
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002330:Carmustine / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D019803:Glutathione Disulfide; D005979:Glutathione Peroxidase / Q000187:drug effects*; D005982:Glutathione Transferase / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000964:Antimetabolites, Antineoplastic; D009124:Muscle Proteins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D005978:Glutathione; D002330:Carmustine; D019803:Glutathione Disulfide