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Dapsone Hydroxylamine, an Active Metabolite of Dapsone, Can Promote the Procoagulant Activity of Red Blood Cells and Thrombosis

Title
Dapsone Hydroxylamine, an Active Metabolite of Dapsone, Can Promote the Procoagulant Activity of Red Blood Cells and Thrombosis
Authors
Bian, YiyingKim, KeunyoungAn, Gwang-JinNgo, ThienBae, Ok-NamLim, Kyung-MinChung, Jin-Ho
Ewha Authors
임경민
SCOPUS Author ID
임경민scopus
Issue Date
2019
Journal Title
TOXICOLOGICAL SCIENCES
ISSN
1096-6080JCR Link

1096-0929JCR Link
Citation
TOXICOLOGICAL SCIENCES vol. 172, no. 2, pp. 435 - 444
Keywords
dapsone hydroxylamine (DDS-NHOH)thrombosisred blood cells (RBCs)phosphatidylserine (PS) exposureprocoagulant activityreactive oxygen species (ROS) generation
Publisher
OXFORD UNIV PRESS
Indexed
SCI; SCIE; SCOPUS WOS
Document Type
Article
Abstract
Dapsone hydroxylamine (DDS-NHOH), N-hydroxylated metabolite of a sulfonamide antibiotic, dapsone, is responsible for various adverse effects of dapsone that include methemoglobinemia, hemolytic anemia, and thrombosis. However, the mechanism underlying DDS-NHOH-induced thrombosis remains unclear. Here, we demonstrated that DDS-NHOH, but not dapsone, could increase prothrombotic risks through inducing the procoagulant activity of red blood cells (RBCs). In freshly isolated human RBCs in vitro, sub-hemolytic concentrations of DDS-NHOH (10-50 mu M) increased phosphatidylserine (PS) exposure and augmented the formation of PS-bearing microvesicles (MV). Reactive oxygen species (ROS) generation and the subsequent dysregulation of enzymes maintaining membrane phospholipid asymmetry were found to induce the procoagulant activity of DDS-NHOH. Dapsone hydroxylamine also accelerated thrombin generation and enhanced RBC self-aggregation and adherence of RBCs to endothelial cells in vitro. Most importantly, both the single dose of 50 or 100 mg/kg (i.p.) DDS-NHOH and repeated doses of 10 mg/kg per day (i.p.) for 4 days increased thrombus formation in rats (six rats per dose) in vivo, substantiating a potential prothrombotic risk of DDS-NHOH. Collectively, these results demonstrated the central role of RBC procoagulant activity induced by DDS-NHOH in the thrombotic risk of dapsone.
DOI
10.1093/toxsci/kfz188
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약학대학 > 약학과 > Journal papers
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