Technical University of Braunschweig, Institute of Pharmacology, Toxicology, and Clinical Pharmacy, Braunschweig, Germany.
Martin-Luther-University Halle-Wittenberg, Department of Clinical Pharmacy and Pharmacotherapy, Halle (Saale), Germany.
Biochem Biophys Res Commun. 2014 Jan 24;443(4):1211-7. doi: 10.1016/j.bbrc.2013.12.119. Epub 2014 Jan 3.
The ATP-binding cassette transporter ABCG2 plays a prominent role in cardiovascular and cancer pathophysiology, is involved in the pathogenesis of gout, and affects pharmacokinetics of numerous drugs. Telmisartan, a widely used AT1 receptor antagonist, inhibits the transport capacity of ABCG2 and may cause drug-drug interactions, especially in individuals carrying polymorphism that facilitate the telmisartan-ABCG2 interaction. Thus, the aim of this study was to identify ABCG2 polymorphisms and somatic mutations with relevance for the telmisartan-ABCG2 interaction. For this purpose, a cellular system for the conditional expression of ABCG2 was established. ABCG2 variants were generated via site-directed mutagenesis. Interaction of telmisartan with these ABCG2 variants was investigated in HEK293-Tet-On cells using the pheophorbide A efflux assay. Moreover, expression of ABCG2 variants was studied in these cells. Importantly, protein levels of the Q141K and F489L variant were significantly reduced, a phenomenon that was partly reversed by pharmacological proteasome inhibition. Moreover, basal pheophorbide A efflux capacity of S248P, F431L, and F489L variants was significantly impaired. Interestingly, inhibition of ABCG2-mediated pheophorbide A transport by telmisartan was almost abolished in cells expressing the R482G variant, whereas it was largely increased in cells expressing the F489L variant. We conclude that the arginine residue at position 482 of the ABCG2 molecule is of major importance for the interaction of telmisartan with this ABC transporter. Furthermore, individuals carrying the F489L polymorphism may be at increased risk of developing adverse drug reactions in multi-drug regimens involving ABCG2 substrates and telmisartan.
三磷酸腺苷结合盒转运体 ABCG2 在心血管和癌症病理生理学中发挥着重要作用，与痛风的发病机制有关，并影响许多药物的药代动力学。替米沙坦是一种广泛使用的 AT1 受体拮抗剂，可抑制 ABCG2 的转运能力，并可能导致药物相互作用，尤其是在携带促进替米沙坦-ABCG2 相互作用的多态性的个体中。因此，本研究旨在确定与替米沙坦-ABCG2 相互作用相关的 ABCG2 多态性和体细胞突变。为此，建立了一个用于 ABCG2 条件表达的细胞系统。通过定点诱变产生 ABCG2 变体。使用 pheophorbide A 外排测定法在 HEK293-Tet-On 细胞中研究替米沙坦与这些 ABCG2 变体的相互作用。此外，还在这些细胞中研究了 ABCG2 变体的表达。重要的是，Q141K 和 F489L 变体的蛋白水平显著降低，这一现象部分被药理学蛋白酶体抑制所逆转。此外，S248P、F431L 和 F489L 变体的基础 pheophorbide A 外排能力显著受损。有趣的是，在表达 R482G 变体的细胞中，替米沙坦抑制 ABCG2 介导的 pheophorbide A 转运几乎被完全消除，而在表达 F489L 变体的细胞中，这种抑制作用则大大增加。我们得出结论，ABCG2 分子中第 482 位的精氨酸残基对替米沙坦与该 ABC 转运体的相互作用至关重要。此外，携带 F489L 多态性的个体可能会增加在涉及 ABCG2 底物和替米沙坦的多药方案中发生不良反应的风险。
