Dabigatran Etexilate Induces Cytotoxicity in Rat Gastric Epithelial Cell Line via Mitochondrial Reactive Oxygen Species Production.

Hiromi Kurokawa,Hidemi Shigekawa,Hirofumi Matsui,Atsushi Taninaka

doi:10.3390/cells10102508

Abstract

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.

Highlights

Dabigatran and warfarin are anticoagulant drugs used to prevent stroke in patients with atrial fibrillation [1]
Cells were stimulated with different concentrations of dabigatran etexilate the WST assay
We investigated the roles of dabigatran etexilate and tartaric acid in order to elucidate theinvestigated mechanism underlying dabigatran cytotoxicity

Summary

Introduction

Dabigatran and warfarin are anticoagulant drugs used to prevent stroke in patients with atrial fibrillation [1]. Warfarin is a vitamin K antagonist that inhibits the activation of clotting factors II, VII, IX, and X [2]. Vitamin K antagonists exhibit multiple interactions with food and drugs; patients who are prescribed these drugs need to be monitored frequently. Dabigatran directly inhibits free and fibrin-bound thrombin and exhibits rapid and predictable anticoagulant effects [4,5]. Dabigatran prevents embolic events in patients with non-hemorrhagic stroke and atrial fibrillation and can be used in a safe and effective manner without the need for monitoring and dose adjustment, in contrast to warfarin, which requires continuous monitoring [6]. Dabigatran is well-tolerated, exhibits predictable pharmacokinetics, and induces effective anticoagulant effects.

Results

Discussion

Conclusion