Enantioselective binding of disopyramide to α1-acid glycoprotein and its variants
Enantioselective binding of disopyramide to α1-acid glycoprotein and its variants
复制标题
丙吡胺与 α1-酸性糖蛋白及其变体的对映选择性结合
DOI：
10.1007/s002280100354
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发表时间：
2001
影响因子：
2.9
通讯作者：
K. Miyazaki
中科院分区：
文献类型：
--
作者：
S. Kishino;S. Itoh;T. Nakagawa;K. Miyazaki
目的：α1-酸性糖蛋白（AAG）有三种主要的遗传变体：F1、S和A变体。关于AAG变异体与药物对映体结合活性之间的相关性报道较少。研究了碱性药物丙吡胺（DP）对映体结合特性的差异。本研究的目的是阐明DP对映体之间结合特性差异的原因。方法：采用羟基磷灰石层析法分离人AAG中的变异体。通过超滤法研究了DP对映体与AAG变体的结合。在0.5 - 50.0 µg/ml浓度范围内，通过Scatchard分析检查DP对映体与总变体和每种变体的结合特征。结果：变体3中S-DP的结合能力显著高于R-DP，尽管变体2中DP对映体的结合能力几乎相同。另一方面，变体3中S-DP和R-DP两者的结合能力显著高于变体2中的那些。此外，在变体3中，S-DP和R-DP之间的解离常数（Kd）几乎相差2.4倍，尽管在结合位点的数目（N）上没有观察到显著差异。在变体2中，未观察到DP对映体之间在解离常数或每分子AAG结合位点数方面存在显著差异。另一方面，观察到变体2和3在S-DP和R-DP的解离常数方面的显著差异。结论：S-DP和R-DP结合能力的差异是由于DP与变体3-6结合的差异，变体1和2在药物与AAG结合中的作用较小。
Objective:α1-Acid glycoprotein (AAG) has three main genetic variants, F1, S, and A variants. There are few reports on the correlation between AAG variants and binding activity of drug enantiomers. We studied the differences between the binding characteristics of enantiomers of disopyramide (DP), which is a basic drug. The aim of this study was to elucidate the cause of the differences between the binding characteristics of DP enantiomers.Methods:The variants in human AAG were separated by hydroxyapatite chromatography. Binding of DP enantiomers to AAG variants was studied by the ultrafiltration method. The characteristics of the binding of DP enantiomers to total variants and each variant were examined by Scatchard analysis within a range of concentrations from 0.5 to 50.0 µg/ml.Results:The binding capacity of S-DP was significantly higher than that of R-DP in variant 3, although the binding capacities of DP enantiomers were almost the same in variant 2. On the other hand, the binding capacities for both S-DP and R-DP in variant 3 were significantly higher than those in variant 2. Furthermore, there was an almost 2.4-fold difference in the dissociation constant (Kd) between S-DP and R-DP in variant 3, although no significant difference was observed in the number of binding sites (N). In variant 2 no significant differences between DP enantiomers were observed in either the dissociation constant or number of binding sites per molecule of AAG. On the other hand, significant differences between variants 2 and 3 in the dissociation constant for both S-DP and R-DP were observed. The differences in dissociation constant between variants 2 and 3 were 4.0-fold in S-DP and 1.7-fold in R-DP.Conclusion:The difference between the binding capacities of S-DP and R-DP is due to differences in the association of DP to variants 3–6, and the role of the variants 1 and 2 in the binding of drugs to AAG is minor.