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阿巴卡韦增强ATP对嘌呤能P2X7受体的激活作用：促炎协同作用是其心血管毒性的潜在原因吗？

Abacavir Increases Purinergic P2X7 Receptor Activation by ATP: Does a Pro-inflammatory Synergism Underlie Its Cardiovascular Toxicity?

作者信息

Collado-Díaz Víctor, Martinez-Cuesta Maria Ángeles, Blanch-Ruiz Maria Amparo, Sánchez-López Ainhoa, García-Martínez Patricia, Peris José E, Usach Iris, Ivorra Maria Dolores, Lacetera Alessandra, Martín-Santamaría Sonsoles, Esplugues Juan V, Alvarez Angeles

机构信息

Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.

CIBERehd, Valencia, Spain.

出版信息

Front Pharmacol. 2021 Mar 31;12:613449. doi: 10.3389/fphar.2021.613449. eCollection 2021.

DOI:10.3389/fphar.2021.613449
PMID:33867979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8045785/
Abstract

The cardiovascular toxicity of Abacavir is related to its purinergic structure. Purinergic P2X7-receptors (P2X7R), characterized by activation by high concentrations of ATP and with high plasticity, seem implicated. We appraise the nature of the interplay between Abacavir and P2X7R in generating vascular inflammation. The effects of Abacavir on leukocyte-endothelium interactions were compared with those of its metabolite carbovir triphosphate (CBV-TP) or ATP in the presence of apyrase (ATP-ase) or A804598 (P2X7R-antagonist). CBV-TP and ATP levels were evaluated by HPLC, while binding of Abacavir, CBV-TP and ATP to P2X7R was assessed by radioligand and docking studies. Hypersensitivity studies explored a potential allosteric action of Abacavir. Clinical concentrations of Abacavir (20 µmol/L) induced leukocyte-endothelial cell interactions by specifically activating P2X7R, but the drug did not show affinity for the P2X7R ATP-binding site (site 1). CBV-TP levels were undetectable in Abacavir-treated cells, while those of ATP were unaltered. The effects of Abacavir were Apyrase-dependent, implying dependence on endogenous ATP. Exogenous ATP induced a profile of proinflammatory actions similar to Abacavir, but was not entirely P2X7R-dependent. Docking calculations suggested ATP-binding to sites 1 and 2, and Abacavir-binding only to allosteric site 2. A combination of concentrations of Abacavir (1 µmol/L) and ATP (0.1 µmol/L) that had no effect when administered separately induced leukocyte-endothelium interactions mediated by P2X7R and involving Connexin43 channels. Therefore, Abacavir acts as a positive allosteric modulator of P2X7R, turning low concentrations of endogenous ATP themselves incapable of stimulating P2X7R into a functional proinflammatory agonist of the receptor.

摘要

阿巴卡韦的心血管毒性与其嘌呤能结构有关。嘌呤能P2X7受体（P2X7R）的特征是被高浓度ATP激活且具有高可塑性，似乎与之相关。我们评估了阿巴卡韦与P2X7R之间相互作用在引发血管炎症中的本质。在存在腺苷三磷酸双磷酸酶（ATP酶）或A804598（P2X7R拮抗剂）的情况下，将阿巴卡韦对白细胞与内皮细胞相互作用的影响与其代谢产物三磷酸卡波韦（CBV-TP）或ATP的影响进行了比较。通过高效液相色谱法评估CBV-TP和ATP水平，同时通过放射性配体和对接研究评估阿巴卡韦、CBV-TP和ATP与P2X7R的结合情况。超敏反应研究探索了阿巴卡韦的潜在变构作用。临床浓度的阿巴卡韦（20微摩尔/升）通过特异性激活P2X7R诱导白细胞与内皮细胞相互作用，但该药物对P2X7R的ATP结合位点（位点1）没有亲和力。在阿巴卡韦处理的细胞中未检测到CBV-TP水平，而ATP水平未改变。阿巴卡韦的作用依赖于腺苷三磷酸双磷酸酶，这意味着依赖内源性ATP。外源性ATP诱导出与阿巴卡韦相似的促炎作用谱，但并不完全依赖于P2X7R。对接计算表明ATP结合在位点1和位点2，而阿巴卡韦仅结合变构位点2。单独给药时无作用的阿巴卡韦浓度（1微摩尔/升）和ATP浓度（0.1微摩尔/升）组合可诱导由P2X7R介导并涉及连接蛋白43通道的白细胞与内皮细胞相互作用。因此，阿巴卡韦作为P2X7R的正变构调节剂，将本身无法刺激P2X7R的低浓度内源性ATP转变为该受体的功能性促炎激动剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/4dea63c7b78c/fphar-12-613449-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/77bae8e9d1a8/fphar-12-613449-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/c3708c098867/fphar-12-613449-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/33d70b094dad/fphar-12-613449-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/f4b065dae571/fphar-12-613449-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/9bc2e3c49c3d/fphar-12-613449-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/c2502e8498b5/fphar-12-613449-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/7cd2f28fb751/fphar-12-613449-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/4dea63c7b78c/fphar-12-613449-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/77bae8e9d1a8/fphar-12-613449-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/c3708c098867/fphar-12-613449-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/33d70b094dad/fphar-12-613449-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/3dac835ff02f/fphar-12-613449-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/f4b065dae571/fphar-12-613449-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/9bc2e3c49c3d/fphar-12-613449-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/c2502e8498b5/fphar-12-613449-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/7cd2f28fb751/fphar-12-613449-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/184b/8045785/4dea63c7b78c/fphar-12-613449-g009.jpg

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