Evidence for the Metabolic Activation of Deferasirox In Vitroand In Vivo
- Resource Type
- Article
- Authors
- Su, Mengdie; Zhao, Yanjia; Li, Mei; Jia, Chenyang; Liu, He; Zhang, Yue; Li, Weiwei; Peng, Ying; Zheng, Jiang
- Source
- Chemical Research in Toxicology; August 2023, Vol. 36 Issue: 8 p1255-1266, 12p
- Subject
- Language
- ISSN
- 0893228X; 15205010
Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS in vitroand in vivoto help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5’-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or N-acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.