Inhibition of Respiratory Burst Activity in Alveolar Macrophages by Bisbenzylisoquinoline Alkaloids: Characterization of Drug-Cell Interaction

Abstract

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) ≊ fangchinoline (FA) > berbamine (BE) ≊ cepharanthine (CE) ≊ 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 ≊ BE ≊ 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 hules 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.