Depletion of glutathione selectively inhibits synthesis of leukotriene C by macrophages.

Abstract

The role of glutathione synthesis and intracellular glutathione content in the formation of leukotriene C (LTC) by mouse peritoneal macrophages was studied. Thirty minutes after the addition of 200 .mu.M of BSO (buthionine sulfoximine; a specific inhibitor of glutathione synthesis) to macrophage cultures, when glutathione synthesis was inhibited .apprx. 80%, the cells responded to a zymosan challenge with a normal release of LTC. During this period, intracellular glutathione stores were not significantly depleted. Cells exposed to BSO for 2 h or more exhibited marked decreases in glutathione levels and a progressive inhibition of LTC synthesis. After exposure to BSO for 16 h, intracellular glutathione was undetectable, and no LTC was synthesized by the cells. Treatment of macrophages with BSO for 16 h had no effect on cell viability, phagocytosis, total release of arachidonic acid or prostaglandin synthesis. An increased synthesis of hydroxyicosatetraenoic acids in BSO-treated cells compensated for the diminished production of LTC. BSO evidently produces a specific, time-dependent inhibition of LTC synthesis as a result of intracellular glutathione depletion. This is consistent with a biosynthetic pathway for LTC in which glutathione is a direct precursor of this arachidonic acid metabolite.