Abacavir Increases Purinergic P2X7 Receptor Activation by ATP: Does a Pro-inflammatory Synergism Underlie Its Cardiovascular Toxicity?
Por:
Collado-Díaz V, Martinez-Cuesta MÁ, Blanch-Ruiz MA, Sánchez-López A, García-Martínez P, Peris JE, Usach I, Ivorra MD, Lacetera A, Martín-Santamaría S, Esplugues JV and Alvarez A
Publicada:
31 mar 2021
Ahead of Print:
31 mar 2021
Resumen:
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 mu mol/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 mu mol/L) and ATP (0.1 mu mol/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.
Filiaciones:
Collado-Díaz V:
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
Martinez-Cuesta MÁ:
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
CIBERehd, Valencia, Spain
Blanch-Ruiz MA:
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
Sánchez-López A:
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
García-Martínez P:
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
Peris JE:
Departamento de Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain
Usach I:
Departamento de Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain
Ivorra MD:
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
Lacetera A:
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
Martín-Santamaría S:
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
:
FISABIO- Fundación Hospital Universitario Dr. Peset, Valencia, Spain
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
CIBERehd, Valencia, Spain
:
CIBERehd, Valencia, Spain
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
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