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 ce llular detoxification system. We studied the effect of GSH depletion b y buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamylcy steine synthetase, on doxorubicin (DOX) toxicity in mice. The administ ration of BSO (30 mM in drinking water for 5 days) significantly decre ased the tissue GSH. The GSH depletion in various tissues by BSO was a ssociated with a decrease in the detoxification of DOX in mice. A sing le dose of 20 mg/kg of DOX significantly reduced body weight and recta l temperature in mice 3 days after injection. The combination with BSO and cepharanthine (biscoclaurine alkaloid), a P-glycoprotein (P-gp) i nhibitor, significantly potentiated decrease in body and hypothermia i nduced 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.