Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1-acid glycoprotein.
Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1-acid glycoprotein.
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药物与人类 α1-酸性糖蛋白的两个主要遗传变体的结合存在差异的证据。
DOI：
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发表时间：
1993
影响因子：
3.4
通讯作者：
J. Tillement
中科院分区：
文献类型：
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作者：
F. Hervé;E. Gomas;J. Duché;J. Tillement
1.人α1-酸性糖蛋白(AAG)是一种血浆转运蛋白，有三种主要的遗传变异。F1.S和A.本地商业AAG(这三个变种的比例几乎相等的混合物)已通过层析分离成对应于人类编码AAG的两个基因的蛋白质的变种：A变种以及F1和S变种的混合物(60%F1和40%S)。用平衡透析法研究了它们与丙咪嗪、华法林和米非司酮的结合特性。2.F_1S变异体与华法林和米非司酮强结合，亲和力分别为1.89和2.06×10~(-6)L摩尔~(-1)，但对丙咪嗪亲和力较低。反之，A变异体与丙咪嗪强结合，亲和力为0.98x10(6)L。华法林和米非司酮与A变异样本结合程度低的原因是该样本中存在蛋白质污染物。这些结果表明了每个变异的特定药物转运作用，相对于其不同的遗传来源。3.用(普通)商品AAG和从具有F1/A或S/A表型的个体分离的AAG进行的对照结合实验与这些发现一致。AAG样品与F1S混合物结合华法林和米非司酮的结果与F1S混合物相似：AAG样品对每种药物的平均高亲和力结合常数与F1S混合物的平均高亲和力结合常数相同；与F1S混合物相比，AAG样品结合位点数的减少是因为这些样品中F1和/或S的变异体所占比例较小。相反，丙咪嗪与AAG样品的结合研究结果与该碱性药物与A变体结合的结果在这些样品中A变体的比例方面是一致的。
1. Human alpha 1-acid glycoprotein (AAG), a plasma transport protein, has three main genetic variants. F1. S and A. Native commercial AAG (a mixture of almost equal proportions of these three variants) has been separated by chromatography into variants which correspond to the proteins of the two genes which code for AAG in humans: the A variant and a mixture of the F1 and S variants (60% F1 and 40% S). Their binding properties towards imipramine, warfarin and mifepristone were studied by equilibrium dialysis. 2. The F1S variant mixture strongly bound warfarin and mifepristone with an affinity of 1.89 and 2.06 x 10(6) l mol-1, respectively, but had a low affinity for imipramine. Conversely, the A variant strongly bound imipramine with an affinity of 0.98 x 10(6) l mol-1. The low degree of binding of warfarin and mifepristone to the A variant sample was explained by the presence of protein contaminants in this sample. These results indicate specific drug transport roles for each variant, with respect to its separate genetic origin. 3. Control binding experiments performed with (unfractionated) commercial AAG and with AAG isolated from individuals with either the F1/A or S/A phenotypes, agreed with these findings. The results for the binding of warfarin and mifepristone by the AAG samples were similar to those obtained with the F1S mixture: the mean high-affinity association constant of the AAG samples for each drug was of the same order as that of the F1S mixture: the decrease in the number of binding sites of the AAG samples, as compared with the F1S mixture, was explained by the smaller proportion of variants F1 and/or S in these samples. Conversely, results of the imipramine binding study with the AAG samples concurred with those for the binding of this basic drug by the A variant, with respect to the proportion of the A variant in these samples.