Ma J K, Mo C G, Malanga C J, Ma J Y, Castranova V
School of Pharmacy, West Virginia University, Morgantown.
Exp Lung Res. 1991 Nov-Dec;17(6):1061-77. doi: 10.3109/01902149109064335.
A group of bisbenzylisoquinoline alkaloids has been shown to exhibit various degrees of effectiveness in preventing silica-induced fibrosis in animal models. The objective of 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 confirmation 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.
一组双苄基异喹啉生物碱已被证明在动物模型中对预防二氧化硅诱导的纤维化具有不同程度的有效性。本研究的目的是分别使用荧光法和平衡透析法来表征其中几种生物碱与磷脂酰胆碱囊泡和大鼠肺泡巨噬细胞的结合情况。发现这些生物碱的脂质结合亲和力取决于几个结构因素，包括疏水取代、手性构型以及苄基异喹啉部分的双氧桥限制构象。汉防己甲素是预防纤维化的高效药物，它与脂质囊泡和肺泡巨噬细胞都有很强的结合。相比之下，汉防己甲素的某些类似物，如箭毒碱和筒箭毒碱，对矽肺几乎没有影响，它们与脂质囊泡的结合较弱，与细胞几乎没有结合。粉防己碱与囊泡和细胞的中等结合亲和力与该化合物作为抗纤维化剂的中等有效性相对应。甲氧基天仙防己碱是一种抗纤维化潜力未知的生物碱，它对脂质和细胞也表现出高结合亲和力。总之，这些研究结果表明肺泡巨噬细胞对这类双苄基异喹啉生物碱的某些成员具有很大的结合能力。观察到与肺泡巨噬细胞的结合亲和力与这些化合物报道的抗纤维化效力之间存在正相关。这些数据还表明，这些药物与肺泡巨噬细胞相互作用的能力可能是抑制二氧化硅诱导的肺部疾病进展的关键步骤。
