Ma J Y, Barger M W, Ma J K, Castranova V
Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, WV 26505.
Exp Lung Res. 1992 Nov-Dec;18(6):829-43. doi: 10.3109/01902149209031710.
The objective of this study was to investigate the effects of various bisbenzylisoquinoline (BBIQ) alkaloids on respiratory burst activity of alveolar macrophages and to characterize the interaction of these drugs with alveolar phagocytes. BBIQ alkaloids were chosen for study because they exhibit a wide range of antifibrotic potencies in a rat model, with tetrandrine being very effective and tubocurarine being ineffective. These drugs inhibited zymosan-stimulated oxygen consumption with a potency sequence of tetrandrine (TT) approximately fangchinoline (FA) > berbamine (BE) approximately cepharanthine (CE) approximately cycleanine (CY) >> tubocurarine (TU). This inhibition of respiratory burst activity could not be attributed to a drug-induced decline in the ATP content of these pneumocytes. Drug binding to alveolar macrophages was directly dependent on temperature and drug concentration. The sequence for binding capacity was FA > TT approximately BE approximately CY > CE >> TU. Therefore, there was no simple relationship between binding capacity and inhibitory potency. Binding capacity was not related to lipophilicity of these alkaloids. In addition, tetrandrine failed to bind to metabolically dead cells or sonicated macrophage preparations. These data suggest that the interaction of BBIQ alkaloids with phagocytes is not simply nonspecific binding to membrane lipids. Alteration of the cytoskeletal system with vinblastine, taxol, or cytochalasin B decreased tetrandrine binding by approximately 33% when added separately and by 93% when added jointly. Pre-exposure of alveolar macrophages to stimulants increased the ability of BBIQ alkaloids to inhibit both oxygen consumption and superoxide release. These data suggest that the mechanism by which BBIQ alkaloids inhibit activation of phagocytes involves microtubules and bules and microfilaments. Pre-exposure of macrophages to stimulants would change the conformation of cytoskeletal components and may make these structures more susceptible to drug interaction.
本研究的目的是调查各种双苄基异喹啉（BBIQ）生物碱对肺泡巨噬细胞呼吸爆发活性的影响，并表征这些药物与肺泡吞噬细胞的相互作用。选择BBIQ生物碱进行研究是因为它们在大鼠模型中表现出广泛的抗纤维化效力，其中粉防己碱非常有效而筒箭毒碱无效。这些药物抑制酵母聚糖刺激的氧消耗，效力顺序为粉防己碱（TT）约汉防己甲素（FA）>小檗胺（BE）约千金藤素（CE）约环轮宁（CY）>>筒箭毒碱（TU）。这种对呼吸爆发活性的抑制不能归因于药物引起的这些肺细胞ATP含量的下降。药物与肺泡巨噬细胞的结合直接取决于温度和药物浓度。结合能力的顺序为FA>TT约BE约CY>CE>>TU。因此，结合能力与抑制效力之间没有简单的关系。结合能力与这些生物碱的亲脂性无关。此外，粉防己碱未能与代谢死亡的细胞或超声处理的巨噬细胞制剂结合。这些数据表明，BBIQ生物碱与吞噬细胞的相互作用不仅仅是与膜脂质的非特异性结合。用长春碱、紫杉醇或细胞松弛素B改变细胞骨架系统，单独添加时粉防己碱结合减少约33%，联合添加时减少93%。肺泡巨噬细胞预先暴露于刺激物会增加BBIQ生物碱抑制氧消耗和超氧化物释放的能力。这些数据表明，BBIQ生物碱抑制吞噬细胞活化的机制涉及微管和微丝。巨噬细胞预先暴露于刺激物会改变细胞骨架成分的构象，并可能使这些结构更容易受到药物相互作用的影响。
