BUTHIONINE SULFOXIMINE-INDUCED GLUTATHIONE DEPLETION - ITS EFFECT ON ANTIOXIDANTS, LIPID-PEROXIDATION AND CALCIUM HOMEOSTASIS IN THE LUNG

The administration of buthionine sulfoximine (BSO), an irreversible in hibitor of gamma-glutamylcysteine synthetase, produces glutathione (GS H) depletion in tumors, making them sensitive to drugs and radiation. During the process, it also depletes GSH from normal tissues. Certain tumors require frequent doses of BSO for several days to produce GSH d epletion. In this study, we determined that this chronic GSH-deficient condition lowers the antioxidant defense of the lung by diminishing t he activities of superoxide dismutase, catalase, and glutathione perox idase and the levels of ascorbic acid and cu-tocopherol. Impaired anti oxidant defense leads to enhanced lipid peroxidation, as indicated by increased levels of thiobarbituric acid reactive substances and conjug ated dienes. The alteration of protein thiols by lipid peroxidation, i s responsible for altered Ca2+ homeostasis, which, in turn, leads to c ell injury. Cell injury was confirmed by elevated activities of angiot ensin converting enzyme and lactate dehydrogenase, increased levels of protein and lactate, and histopathological changes.