Cytotoxicity to macrophages of tetrandrine, an antisilicosis alkaloid, accompanied by an overproduction of prostaglandins.
Tetrandrine, an anti-inflammatory immunosuppressive bisbenzylisoquinoline alkaloid of Chinese herbal origin, is widely used to treat silicosis and interferes with the regulation of calcium in many cell types. We investigated its effect on the cellular integrity of macrophages and on their ability to generate prostaglandins and nitric oxide, mediators of inflammation with immunomodulatory roles. Tetrandrine at 10(-7) M to 10(-4) M caused dose- and time-dependent loss of cell viability of mouse peritoneal macrophages, guinea-pig alveolar macrophages and mouse macrophage-like J774 cells. Loss of viability (50%) occurred within 1-3 hr and required approximately 5 x 10(-6) M tetrandrine. Loss of macrophage viability after tetrandrine treatment was accompanied by the generation of large amounts of prostaglandin E2 (PGE2), to levels 285-877% of control. Coincubation with indomethacin abolished PGE2 generation, but did not prevent cell death. Tetrandrine did not cause generation of nitric oxide. Verapamil also reduced the viability of mouse peritoneal macrophages and J774 cells, but did not cause PGE2 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 PGE2 and nitric oxide, tetrandrine reduced mediator release and their forming enzymes (cyclo-oxygenase-2 and inducible nitric oxide synthase), secondary to cytotoxicity. The predominant action of tetrandrine is to exert a cytotoxic effect on macrophages, perhaps by interfering with calcium homeostasis; this leads to overproduction of immunomodulatory but proinflammatory prostaglandin. This may be relevant to its protective actions in human fibrosing silicosis, in which there is alveolar macrophage involvement.
Pang
L
L
Pharmacology Group, King's College London, U.K.
Hoult
J R
JR
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D044182:Benzylisoquinolines; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007527:Isoenzymes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D012829:Silicosis / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014700:Verapamil / Q000494:pharmacology
D000470:Alkaloids; D044182:Benzylisoquinolines; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; C009438:tetrandrine; D009569:Nitric Oxide; D014700:Verapamil; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone