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 inhibitor of gamma-glutamylcysteine synthetase, produces glutathione (GSH) 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 depletion. In this study, we determined that this chronic GSH-deficient condition lowers the antioxidant defense of the lung by diminishing the activities of superoxide dismutase, catalase, and glutathione peroxidase and the levels of ascorbic acid and alpha-tocopherol. Impaired antioxidant defense leads to enhanced lipid peroxidation, as indicated by increased levels of thiobarbituric acid reactive substances and conjugated dienes. The alteration of protein thiols by lipid peroxidation, is responsible for altered Ca2+ homeostasis, which, in turn, leads to cell injury. Cell injury was confirmed by elevated activities of angiotensin converting enzyme and lactate dehydrogenase, increased levels of protein and lactate, and histopathological changes.