Studies Of The Binding Of Bisbenzylisoquinoline Alkaloids To Phosphatidylcholine Vesicles And Alveolar Macrophages In Relation To Their Antifibrogenic Potential

A group of bisbenzylisoquinoline (BBIQ) alkaloids has been shown to exhibit various degrees of effectiveness in preventing silicainduced fibrosis in animal models (1, 2). The capability of these drugs to interact with phosphatidycholine vesicles and rat alveolar macrophages was studied using fluorometric and equilibrium dialysis methods. The lipid binding affinity of these alkaloids was found to depend upon several structural factors including hydrophobic substitutions, the chiral configurations, and the double oxygen bridge-restricted conformation of the benzylisoquinoline moieties. Tetrandrine, which is highly effective in preventing fibrosis, showed strong binding to both lipid vesicles and alveolar macrophages. In contrast, curine and tubocurine, which have little or no effect on silicosis, exhibited only weak binding to lipid vesicles and almost no binding to cells. The moderate binding affinity of fangchinoline to vesicles and cells corresponded to a moderate effectiveness of the compound as an antifibrogenic agent. Methoxyadiantifoline, an alkaloid of unknown antifibrogenic potential, also exhibited high binding affinities for lipid and cells. In summary, this study indicates that alveolar macrophages exhibit large binding capacities for certain members of the BBIQ alkaloids. A positive correlation was observed between binding affinity to alveolar macrophages and the reported antifibrotic potency of these compounds, suggesting that the ability of these drugs to interact with alveolar macrophages may be a key step in inhibition of the progression of silica-induced pulmonary disease.