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首页> 外文期刊>Pharmacogenetics and genomics >A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity.
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A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity.

机译：在人类血管紧张素II 1型受体的163位上，丙氨酸与苏氨酸的单核苷酸多态性损害了氯沙坦的亲和力。

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摘要

BACKGROUND AND OBJECTIVE: AT1 is the principal receptor for angiotensin II (AngII), which regulates blood pressure and osmotic homeostasis. Earlier studies have shown that position 163 interacts with the antihypertensive nonpeptide antagonist, Losartan. A recently discovered polymorphism found in humans (rs12721226) coding for residue 163 led us to determine whether this polymorphism would affect Losartan antihypertensive therapies. The pharmacological properties of the A163T hAT1 variant are described. METHOD AND RESULTS: The A163T hAT1 mutation was evaluated by testing its affinity by dose displacement of AngII analogs in COS-7 cells expressing either wild-type hAT1 or the A163T hAT1. The expressions of the receptors were evaluated by saturation binding and the efficacies were assessed by measuring the 3H-inositol phosphate production. The results showed that the A163T hAT1 receptor is comparable with the affinity, expression, and efficacy of native hAT1 towards peptide ligands. The affinities were also tested with nonpeptide antagonists Losartan, L-158 809, valsartan, telmisartan, irbesartan, candesartan, and EXP3174. Losartan and EXP3174 displayed a 7-fold loss in affinity towards A163T hAT1. The ability of Losartan to inhibit AngII-induced inositol triphosphate production also confirmed a loss in efficacy. Molecular modeling showed a higher steric and hydrophilic hindrance of the A163T hAT1-Losartan complex. CONCLUSION: The polymorphism that codes for the A163T hAT1 variant results in a receptor with normal physiological properties toward the endogenous hormone. However, the significant reduction in affinity to Losartan and its active metabolite, EXP3174, could significantly impair the clinical effectiveness of an antihypertensive therapy using Losartan with patients bearing the A163T polymorphism.
机译：背景与目的：AT1是血管紧张素II（AngII）的主要受体，血管紧张素II调节血压和渗透稳态。较早的研究表明，位置163与降压非肽拮抗剂洛沙坦相互作用。最近在人类中发现的编码残基163的多态性（rs12721226）使我们确定这种多态性是否会影响Losartan降压疗法。描述了A163T hAT1变体的药理特性。方法和结果：通过在表达野生型hAT1或A163T hAT1的COS-7细胞中AngII类似物的剂量置换来测试其亲和力，从而评估A163T hAT1突变。通过饱和结合评估受体的表达，并通过测量3H-肌醇磷酸产生来评估功效。结果表明，A163T hAT1受体与天然hAT1对肽配体的亲和力，表达和功效相当。还使用非肽拮抗剂Losartan，L-158 809，缬沙坦，替米沙坦，厄贝沙坦，坎地沙坦和EXP3174测试了亲和力。 Losartan和EXP3174对A163T hAT1的亲和力降低了7倍。氯沙坦抑制AngII诱导的肌醇三磷酸生成的能力也证实了功效的降低。分子模型表明，A163T hAT1-Losartan复合物的空间和亲水位阻较高。结论：编码A163T hAT1变体的多态性导致受体对内源激素具有正常的生理特性。但是，与氯沙坦及其活性代谢物EXP3174的亲和力显着降低，可能会严重削弱使用氯沙坦治疗患有A163T多态性患者的降压治疗的临床效果。

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