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

Yiying Bian, Keunyoung Kim, Gwang Jin An, Thien Ngo, Ok Nam Bae, Kyung Min Lim, Jin Ho Chung

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 μM) 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.

Original languageEnglish
Pages (from-to)435-444
Number of pages10
JournalToxicological Sciences
Volume172
Issue number2
DOIs
StatePublished - 1 Dec 2019

Keywords

  • dapsone hydroxylamine (DDS-NHOH)
  • phosphatidylserine (PS) exposure
  • procoagulant activity
  • reactive oxygen species (ROS) generation
  • red blood cells (RBCs)
  • thrombosis

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