INDUCTION OF APOPTOTIC CELL-DEATH BY METHYLGLYOXAL AND 3-DEOXYGLUCOSONE IN MACROPHAGE-DERIVED CELL-LINES

Production of 2-oxoaldehyde compounds increases during hyperglycemic c onditions and is cytotoxic to susceptible cells. We have investigated the effects of methylglyoxal and 3-deoxyglucosone at physiological con centrations on monocytic leukemia U937 cells and other cell lines. Bot h ladder formation of DNA and nuclear fragmentation were observed in t he cells treated with these agents, indicating that apoptotic cell dea th was induced. The fluorescent intensity of an oxidation sensitive dy e (2',7'-dichlorofluorescin) was increased in U937 cells but not in ot her cells in which apoptosis was not induced. The levels of intracellu lar glutathione, however, were only slightly changed. Apoptosis and in tracellular oxidant levels were enhanced by buthionine sulfoximine, an inhibitor of glutathione biosynthesis, and partially blocked by N-ace tylcysteine, an antioxidant. Thus, it is conceivable that elevation of intracellular oxidant stress is a cause of the apoptosis induced by c ytotoxic 2-oxoaldehyde compounds. (C) 1996 Academic Press, Inc.