Metabolic activation of deferiprone mediated by CYP2A6

Deferiprone (DFP) is a metal chelating agent generally used to treat patients with thalassaemia, due to iron overload in clinical settings.Studies have revealed that long-term use of DFP can induce hepatotoxicity, however, mechanisms of its toxic action remain unclear. The present studies are aimed to characterize the reactive metabolite of DFP, to define the metabolic pathway, and to determine the P450 enzymes participating in the bioactivation.A demethylation metabolite (M1) was observed in rat liver microsomal incubations. Additionally, a glutathione (GSH) conjugate (M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in microsomal incubations fortified with DFP and GSH/NAC.Biliary M2 and urinary M3 were respectively found in animals administered DFP.CYP2A6 enzyme dominated the catalysis to bioactivate DFP.