Binding of Bisbenzylisoquinoline Alkaloids to Phosphatidycholine Vesicles and Alveolar Macrophages: Relationship between Binding Affinity and Antifibrogenic Potential of these Drugs

"A group of bisbenzylisoouinoline alkaloids has been shown to exhibit various degrees of effectiveness in preventing silica-induced fibrosis in animal models [1, 2]. The objective the present study was to characterize the binding of several of these alkaloids to phosphatidylcholine vesicles and rat alveolar macrophages using fluorometric and equilibrium dialysis methods, respectively. The lipid binding affinity of these alkaloids was found to depend upon several structural factors including hydrophobic substitutions, chiral configurations, and double oxygen bridge-restricted conformation of the benzylisoquinoline moieties. Tetrandrine, which is a highly effective agent in preventing fibrosis, showed strong binding to both lipid vesicles and alveolar macrophages. In contrast, certain analogues of tetrandrine such as 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 conclusion, the results of these studies indicate that alveolar macrophages exhibit large binding capacities for certain members of this class of bisbenzylisoquinoline alkaloids. A positive correlation was observed between binding affinity to alveolar macrophages and the reported antifibrotic potency of these compounds. These data also suggest 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.INTRODUCTIONInhalation of crystalline silica is associated with the development of silicosis. This fibrotic disease is characterized by the appearance of concentric hyalinized nodular lesions in the lungs with the progressive development of pulmonary dysfunction [3, 4]. Many theories concerning the etiology of silicosis involve silica-induced activation of alveolar macrophages. Evidence indicates that in vitro silica exposures result in the generation of chemiluminescence, and the release of superoxide and hydrogen peroxide from alveolar macrophages [5]. Activation of alveolar macrophages has also been demonstrated after intratracheal instillation or inhalation of silica [5, 6]. Such excess release of reactive products from pulmonary phagocytes has been associated with damage to the lung parenchyma [7, 8]. In addition, silica exposure results in the release of mediators from alveolar macrophages, which enhance proliferation of fibroblasts and collagen synthesis by these pneumocytes [9-12]."