Pang L, Hoult J R
Pharmacology Group, King's College London, U.K.
Biochem Pharmacol. 1997 Mar 21;53(6):773-82. doi: 10.1016/s0006-2952(96)00817-9.
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.
粉防己碱是一种源自中草药的具有抗炎免疫抑制作用的双苄基异喹啉生物碱，广泛用于治疗矽肺，并能干扰多种细胞类型中钙的调节。我们研究了其对巨噬细胞细胞完整性及其产生前列腺素和一氧化氮能力的影响，前列腺素和一氧化氮是具有免疫调节作用的炎症介质。10^(-7)M至10^(-4)M的粉防己碱导致小鼠腹腔巨噬细胞、豚鼠肺泡巨噬细胞和小鼠巨噬细胞样J774细胞的细胞活力呈剂量和时间依赖性丧失。在1 - 3小时内出现50%的活力丧失，这需要约5×10^(-6)M的粉防己碱。粉防己碱处理后巨噬细胞活力丧失伴随着大量前列腺素E2（PGE2）的产生，达到对照水平的285 - 877%。与吲哚美辛共同孵育可消除PGE2的产生，但不能阻止细胞死亡。粉防己碱不会导致一氧化氮的产生。维拉帕米也会降低小鼠腹腔巨噬细胞和J774细胞的活力，但除了在10^(-4)M浓度下对小鼠腹腔巨噬细胞外，不会导致PGE2过量产生。在用脂多糖和干扰素-γ培养巨噬细胞以诱导大量PGE2和一氧化氮产生的实验中，粉防己碱在细胞毒性继发作用下减少了介质释放及其形成酶（环氧化酶-2和诱导型一氧化氮合酶）。粉防己碱的主要作用是对巨噬细胞发挥细胞毒性作用，可能是通过干扰钙稳态；这导致具有免疫调节作用但促炎的前列腺素过量产生。这可能与其在人类纤维化矽肺中的保护作用相关，在矽肺中存在肺泡巨噬细胞的参与。
