Journal
CELLS
Volume 10, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/cells10102508
Keywords
dabigatran etexilate; mitochondrial reactive oxygen species; lipid peroxidation; atomic force microscopy; antioxidant
Categories
Funding
- JSPS [JP17H06088, JP19H02591, JP19K16854]
- CREST [JPMJCR1875]
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Dabigatran is a novel oral anticoagulant that inhibits thrombins, but its use may increase the risk of gastrointestinal bleeding. Research has shown that its main component, dabigatran etexilate, exhibits cytotoxicity that can be inhibited by ascorbic acid. These cytotoxic effects are likely mediated via mitROS production.
Dabigatran is a novel oral anticoagulant that directly inhibits free and fibrin-bound thrombins and exerts rapid and predictable anticoagulant effects. While the use of this reagent has been associated with an increased risk of gastrointestinal bleeding, the reason why dabigatran use increases gastrointestinal bleeding risk remains unknown. We investigated the cytotoxicity of dabigatran etexilate and tartaric acid, the two primary components of dabigatran. The cytotoxicity of dabigatran etexilate and tartaric acid was measured in a cell viability assay. Intracellular mitochondrial reactive oxygen species (mitROS) production and lipid peroxidation were measured using fluorescence dyes. Cell membrane viscosity was measured using atomic force microscopy. The potential of ascorbic acid as an inhibitor of dabigatran cytotoxicity was also evaluated. The cytotoxicity of dabigatran etexilate was higher than that of tartaric acid. Dabigatran etexilate induced mitROS production and lipid peroxidation and altered the cell membrane viscosity. Ascorbic acid inhibited the cytotoxicity and mitROS production induced by dabigatran etexilate. Therefore, we attributed the cytotoxicity of dabigatran to dabigatran etexilate, and proposed that the cytotoxic effects of dabigatran etexilate are mediated via mitROS production. Additionally, we demonstrated that dabigatran cytotoxicity can be prevented via antioxidant treatment.
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