Aspirin Extrusion From Human Platelets Through Multidrug Resistance Protein-4–Mediated Transport

Mattiello, Teresa; Guerriero, Raffaella; Lotti, Lavinia Vittoria; Trifirò, Elisabetta; Felli, María Pía; Barbarulo, Alessandro; Pucci, Bruna; Gazzaniga, Paola; Gaudio, Carlo; Frati, Luigi; Pulcinelli, Fabio M.

doi:10.1016/j.jacc.2011.03.049

Cited by 76 publications

(29 citation statements)

References 29 publications

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“…Previously, we demonstrated that platelet MRP4 overexpression reduces aspirin‐induced COX‐1 inhibition for its ability to extrude this drug from platelets 20. We also demonstrated that both in vitro and in vivo aspirin treatment induces MRP4 upregulation through the activation of nuclear receptor PPARα 6…”

Section: Resultsmentioning

confidence: 70%

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Massimi

Alemanno

Guarino

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundA mechanism involved in high on‐aspirin treatment residual platelet reactivity is platelet multidrug resistance protein 4 (MRP4) overexpression. Aspirin enhances platelet MRP4 expression with a PPARα‐dependent mechanism and reduces miR‐21 expression that, in turn, downregulates PPARα expression.ObjectiveThe aim of our study was to verify the relationship between miR‐21 and MRP4‐PPARα levels induced by aspirin treatment.MethodsWe evaluated the changes in MRP4‐PPARα, mRNA, MRP4 protein, and miR‐21 expression induced by aspirin in: (i) in vitro–treated megakaryoblastic cell line (DAMI), (ii) primary megakaryocytes cultures and derived platelets, (iii) healthy volunteers’ platelets treated with aspirin, and (iv) aspirinated patients (aspirin‐treated patients) and in a control population (control).ResultsWe observed an aspirin‐induced reverse relationship between the expression of miR‐21 and PPARα‐MRP4. In DAMI cells the miR‐21 mimic transfection reduces PPARα and MRP4 expression, even if cells were treated with aspirin after transfection. MiR‐21 inhibitor transfection induces PPARα and MRP4 expression that are not enhanced by aspirin treatment. In human megakaryocytes, aspirin treatment lead to a miR‐21 downregulation and a MRP4 upregulation and this trend is confirmed in derived platelets. In aspirin‐treated volunteers, an inverse relationship between miR‐21 and MRP4 platelet expression was found after aspirin treatment. A similar negative relationship was found in aspirin‐treated patients vs the control population.ConclusionThe results reported in this study provide information that aspirin induces the modulation of platelet miR‐21 expression levels and this modulation can be responsible for MRP4 enhancement in circulating platelets.

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Section: Resultsmentioning

confidence: 70%

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Massimi

Alemanno

Guarino

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…In this context, it should be pointed out that lyophilic derivatives of intracellular fluorescent probes are substrates of P-glycoprotein (Pgp) and MRP1 [47]. Furthermore, MDR expression is affected by intracellular variation of glutathione (GSH) [61] and oxidative stress [62–65], as well as by various dietary factors [66–69], inflammatory cytokines [70–72], disease states [73–75], and drugs [76–81]. In particular, aspirin, indomethacin, and ibuprofen are substrates for MRP4 [76] and may interfere with fluorescent probe staining.…”

Section: Measurement Of Reactive Species In Leukocytes and Platelementioning

confidence: 99%

Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans

Marrocco

Altieri

Peluso

2017

Oxidative Medicine and Cellular Longevity

565

500

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Oxidative stress is the result of the imbalance between reactive oxygen species (ROS) formation and enzymatic and nonenzymatic antioxidants. Biomarkers of oxidative stress are relevant in the evaluation of the disease status and of the health-enhancing effects of antioxidants. We aim to discuss the major methodological bias of methods used for the evaluation of oxidative stress in humans. There is a lack of consensus concerning the validation, standardization, and reproducibility of methods for the measurement of the following: (1) ROS in leukocytes and platelets by flow cytometry, (2) markers based on ROS-induced modifications of lipids, DNA, and proteins, (3) enzymatic players of redox status, and (4) total antioxidant capacity of human body fluids. It has been suggested that the bias of each method could be overcome by using indexes of oxidative stress that include more than one marker. However, the choice of the markers considered in the global index should be dictated by the aim of the study and its design, as well as by the clinical relevance in the selected subjects. In conclusion, the clinical significance of biomarkers of oxidative stress in humans must come from a critical analysis of the markers that should give an overall index of redox status in particular conditions.

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“…Thus, there are distinct substrate specificity, inhibitors, and tissue distribution as compared to P-glycoprotein. Mainly, three of MRPs are known to interact with the pathways of pain: MRP2/ABCC2, which transfers diclofenac's metabolites [55, 99], MRP3/ABCC3, which was shown to transfer morphine [101], and diclofenac's glucuronides [99], and MRP4/ABCC4, which transports most prostaglandins [222] (even proposed as prostanoid export pump [223, 224]) and acetylsalicylic acid [225, 226]. …”

Section: Drug Transportmentioning

confidence: 99%

Pharmacogenetics of Chronic Pain and Its Treatment

Světlík

Hronová

Bakhouche

et al. 2013

Mediators of Inflammation

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This paper reviews the impact of genetic variability of drug metabolizing enzymes, transporters, receptors, and pathways involved in chronic pain perception on the efficacy and safety of analgesics and other drugs used for chronic pain treatment. Several candidate genes have been identified in the literature, while there is usually only limited clinical evidence substantiating for the penetration of the testing for these candidate biomarkers into the clinical practice. Further, the pain-perception regulation and modulation are still not fully understood, and thus more complex knowledge of genetic and epigenetic background for analgesia will be needed prior to the clinical use of the candidate genetic biomarkers.

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Aspirin Extrusion From Human Platelets Through Multidrug Resistance Protein-4–Mediated Transport

Cited by 76 publications

References 29 publications

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans

Pharmacogenetics of Chronic Pain and Its Treatment

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