EFFECT OF GLUTATHIONE DEPLETION BY BUTHIONINE SULFOXIMINE ON DOXORUBICIN TOXICITY IN MICE

The role of the glutathione (GSH) system in vivo or in drug resistance has received much attention, since GSH is a major component of the cellular detoxification system. We studied the effect of GSH depletion by buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine synthetase, on doxorubicin (DOX) toxicity in mice. The administration of BSO (30 mM in drinking water for 5 days) significantly decreased the tissue GSH. The GSH depletion in various tissues by BSO was associated with a decrease in the detoxification of DOX in mice. A single dose of 20 mg/kg of DOX significantly reduced body weight and rectal temperature in mice 3 days after injection. The combination with BSO and cepharanthine (biscoclaurine alkaloid), a P-glycoprotein (P-gp) inhibitor, significantly potentiated decrease in body and hypothermia induced by DOX. The study demonstrates that BSO markedly increases the toxicological effect of DOX with the alterations in GSH of tissues and suggests that the intracellular accumulation of DOX is not a factor.