Abstract

The intracellular glutathione concentration of intact organisms is normally maintained within certain fixed limits that are characteristic of each cell or tissue type. In this homeostatic condition, the rate of tripeptide's biosynthesis is precisely balanced by the rate of its utilization. If the rate of glutathione utilization is increased—e.g., by the presence of glutathione S-transferase substrates or by a high extracellular amino acid concentration, or if glutathione biosynthesis is slowed—the intracellular concentration of glutathione will decrease. Glutathione biosynthesis is most effectively inhibited by buthionine sulfoximine, a tightly bound inhibitor of γ-glutamylcysteine synthetase, the enzyme catalyzing the first step of glutathione biosynthesis. The synthesis of buthionine sulfoximine, its mode of action, and the procedures for its use in vitro and in vivo are described in the chapter. The incorporation of buthionine sulfoximine into the culture medium of isolated cells produce dramatic drop in the total intracellular glutathione content. The effect observed is dependent on the rate at which buthionine sulfoximine penetrates the cells and the rate at which glutathione is consumed or released by the cells. Buthionine sulfoximine can also be administered to mice or rats by subcutaneous or intraperitoneal injection; neutral solutions containing 50 to 200 mM buthionine sulfoximine are generally appropriate.

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