Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan.
Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8573, Japan.
Cells. 2021 Sep 22;10(10):2508. doi: 10.3390/cells10102508.
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.
达比加群酯是一种新型的口服抗凝剂，可直接抑制游离型和纤维蛋白结合型凝血酶，发挥快速、可预测的抗凝作用。虽然该试剂的使用与胃肠道出血风险增加相关，但达比加群酯增加胃肠道出血风险的原因尚不清楚。我们研究了达比加群酯和酒石酸这两种达比加群主要成分的细胞毒性。通过细胞活力测定法测量达比加群酯和酒石酸的细胞毒性。使用荧光染料测量细胞内线粒体活性氧（mitROS）的产生和脂质过氧化。通过原子力显微镜测量细胞膜粘度。还评估了抗坏血酸作为达比加群酯细胞毒性抑制剂的潜力。达比加群酯的细胞毒性高于酒石酸。达比加群酯诱导 mitROS 的产生和脂质过氧化，并改变细胞膜的粘度。抗坏血酸抑制了达比加群酯诱导的细胞毒性和 mitROS 的产生。因此，我们将达比加群的细胞毒性归因于达比加群酯，并提出达比加群酯的细胞毒性作用是通过 mitROS 的产生介导的。此外，我们证明通过抗氧化剂处理可以预防达比加群的细胞毒性。
