Abstract

1. Deferiprone (DFP) is a metal chelating agent generally used to treat patients with thalassaemia, due to iron overload in clinical settings.

2. 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.

3. 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.

4. Biliary M2 and urinary M3 were respectively found in animals administered DFP.

5. CYP2A6 enzyme dominated the catalysis to bioactivate DFP.

摘要

1. 去铁酮 (DFP) 是一种金属螯合剂，通常用于治疗由于临床环境中铁过载而导致的地中海贫血患者。

2. 研究表明，长期使用 DFP 可引起肝毒性，但其毒性作用机制尚不清楚。目前的研究旨在表征 DFP 的反应性代谢物，定义代谢途径，并确定参与生物活化的 P450 酶。

3. 在大鼠肝微粒体孵育中观察到去甲基化代谢物 (M1)。此外，在用 DFP 和 GSH/NAC 强化的微粒体孵育中检测到谷胱甘肽 (GSH) 偶联物​​ (M2) 和 N-乙酰半胱氨酸 (NAC) 偶联物​​ (M3)。

4. 在施用 DFP 的动物中分别发现胆汁 M2 和尿液 M3。

5. CYP2A6 酶主导生物激活 DFP 的催化作用。