CYTOTOXICITY TO MACROPHAGES OF TETRANDRINE, AN ANTISILICOSIS ALKALOID, ACCOMPANIED BY AN OVERPRODUCTION OF PROSTAGLANDINS

Tetrandrine, an anti-inflammatory immunosuppressive bisbenzylisoquinol ine alkaloid of Chinese herbal origin, is widely used to treat silicos is and interferes with the regulation of calcium in many cell types. W e investigated its effect on the cellular integrity of macrophages and on their ability to generate prostaglandins and nitric oxide, mediato rs of inflammation with immunomodulatory roles. Tetrandrine at 10(-7) M to 10(-4) M caused dose- and time-dependent loss of cell viability o f mouse peritoneal macrophages, guinea-pig alveolar macrophages and mo use macrophage-like J774 cells. Loss of viability (50%) occurred withi n 1-3 hr and required approximate to 5 x 10(-6) M tetrandrine. Loss of macrophage viability after tetrandrine treatment was accompanied by t he generation of large amounts of prostaglandin E(2) (PGE(2)), to leve ls 285-877% of control. Coincubation with indomethacin abolished PGE(2 ) generation, but did not prevent cell death. Tetrandrine did not caus e generation of nitric oxide. Verapamil also reduced the viability of mouse peritoneal macrophages and J774 cells, but did not cause PGE(2) overproduction, except at 10(-4) M in mouse peritoneal macrophages. In macrophages cultured with lipopolysaccharide and interferon-gamma to induce the generation of large amounts of both PGE(2) and nitric oxide , tetrandrine reduced mediator release and their forming enzymes (cycl o-oxygenase-2 and inducible nitric oxide synthase), secondary to cytot oxicity. The predominant action of tetrandrine is to exert a cytotoxic effect on macrophages, perhaps by interfering with calcium homeostasi s; this leads to overproduction of immunomodulatory but proinflammator y prostaglandin. This may be relevant to its protective actions in hum an fibrosing silicosis, in which there is alveolar macrophage involvem ent. (C) 1997 Elsevier Science Inc.