Dapsone Hydroxylamine, an Active Metabolite of Dapsone, Can Promote the Procoagulant Activity of Red Blood Cells and Thrombosis
- 주제(키워드) dapsone hydroxylamine (DDS-NHOH) , thrombosis , red blood cells (RBCs) , phosphatidylserine (PS) exposure , procoagulant activity , reactive oxygen species (ROS) generation
- 주제(기타) Toxicology
- 설명문(일반) [Bian, Yiying; Kim, Keunyoung; An, Gwang-Jin; Ngo, Thien; Chung, Jin-Ho] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea; [Bian, Yiying] China Med Univ, Sch Publ Hlth, Shenyang 110122, Liaoning, Peoples R China; [Bae, Ok-Nam] Hanyang Univ, Coll Pharm, Ansan 426791, Gyeonggido, South Korea; [Lim, Kyung-Min] Ewha Womans Univ, Coll Pharm, Seoul 120750, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 OXFORD UNIV PRESS
- 발행년도 2019
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000165891
- 본문언어 영어
- Published As http://dx.doi.org/10.1093/toxsci/kfz188
- PubMed https://pubmed.ncbi.nlm.nih.gov/31428780
초록/요약
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.
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