A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity

作者：Arsenault Jason; Lehoux Julie; Lanthier Luc; Cabana Jerome; Guillemette Gaetan; Lavigne Pierre; Leduc Richard; Escher Emanuel^*

来源：Pharmacogenetics and Genomics, 2010, 20(6): 377-388.

DOI：10.1097/FPC.0b013e32833a6d4a

• angiotensin II
• EXP3174
• hAT1
• hypertension
• Losartan
• single-nucleotide polymorphism

Background and objective AT(1) 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 hAT(1) variant are described.
Method and results The A163T hAT(1) mutation was evaluated by testing its affinity by dose displacement of AngII analogs in COS-7 cells expressing either wild-type hAT(1) or the A163T hAT(1). The expressions of the receptors were evaluated by saturation binding and the efficacies were assessed by measuring the H-3-inositol phosphate production. The results showed that the A163T hAT(1) receptor is comparable with the affinity, expression, and efficacy of native hAT(1) 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 hAT(1). 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 hAT(1)-Losartan complex.
Conclusion The polymorphism that codes for the A163T hAT(1) 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.

• 出版日期2010-6