Effect of oxidation of low-density lipoprotein on drug binding affinity studied by high performance frontal analysis-capillary electrophoresis
Effect of oxidation of low-density lipoprotein on drug binding affinity studied by high performance frontal analysis-capillary electrophoresis
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DOI：
10.1002/1522-2683(200109)22:16
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发表时间：
2001-10-01
期刊：
影响因子：
2.9
通讯作者：
Nakagawa, T
中科院分区：
文献类型：
--
作者：
Kuroda, Y;Cao, B;Nakagawa, T
采用高效前沿分析-毛细管电泳法（HPFA-CE）研究了低密度脂蛋白（LDL）氧化对药物对映选择性结合亲和力的影响。维拉帕米和尼伐地平对映体被用作手性模型药物。LDL在37 ℃下用硫酸铜氧化0、0.5、1、2和12 h。HPFA-CE方法能够微量测定天然和氧化LDL溶液中的未结合药物浓度。结果发现，LDL与模型药物之间的结合在任何氧化阶段都不是对映选择性的。氧化0.5、1、2和12 h后，LDL和维拉帕米对映体之间的总结合亲和力（nK）分别增加了3.3、4.6、7.0和19倍，而尼伐地平和LDL之间的nK值在相同的反应时间内分别增加了1.3、1.4、1.4和1.7倍。这些结果表明LDL氧化增强了药物结合亲和力，维拉帕米的亲和力比尼伐地平更敏感。各模型药物的nK值在第一个2 h氧化后急剧增加，随后在接下来的10 h氧化后逐渐增加。据认为，净增加的负电荷和/或氢过氧化物的形成，在第一个2小时的氧化增强了药物-LDL的结合更显着的醛或席夫碱的形成，在以下10 In氧化。
The effect of oxidation of low-density lipoprotein (LDL) on the enantioselective drug binding affinity was investigated using high performance frontal analysis - capillary electrophoresis (HPFA-CE). Verapamil and nivadipine enantiomers were used as the chiral model drugs. LDL was oxidized with copper sulfate for 0, 0.5, 1, 2, and 12 h at 37 degreesC. The HPFA-CE method enabled microdetermination of unbound drug concentrations in native and oxidized LDL solutions. It was found that the bindings between LDL and the model drugs were not enantioselective at any oxidation stage. The total binding affinity (nK) between LDL and verapamil enantiomers was increased by 3.3-, 4.6-, 7.0-, and 19-fold after 0.5, 1, 2, and 12 h oxidation, respectively, whereas the nK value between nilvadipine and LDL was increased by 1.3-,1.4-,1.4-, and 1.7-fold in the same reaction times, respectively. These results indicate that the LDL oxidation enhances the drug binding affinity, and the affinity of verapamil is increased more sensitively than that of nilvadipine. The nK value of each model drug increased steeply after the first 2 h oxidation, followed by the gradual increase after the next 10 h oxidation. It is considered that the net increase in the negative charges and/or the formation of hydroperoxides in the first 2 h oxidation enhances the drug-LDL binding more significantly than the formation of aldehydes or Schiff bases in the following 10 In oxidation.