Matsuzaki Yasushi, Nagai Daichi, Ichimura Eiji, Goda Rika, Tomura Arihiro, Doi Mikio, Nishikawa Kiyohiro
Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
J Gastroenterol. 2006 Mar;41(3):231-9. doi: 10.1007/s00535-005-1749-y.
Flutamide, a nonsteroidal antiandrogen used for treatment of prostate cancer, causes a temporary increase in transaminase and in some cases severe liver dysfunction. It is dominantly metabolized by cytochrome P450 (CYP) 1A2 into 2-hydroxyflutamide (OH-flutamide), which has stronger antiandrogenic activity without obvious cytotoxicity to cultured hepatocytes. We hypothesized that another subsidiary metabolite might be responsible for induction of hepatotoxicity.
Flutamide was administered daily to CYP1A2 knockout mice and parental SV129 mice to compare pharmacokinetics and appearance of hepatic toxicity.
In the CYP1A2 knockout mice, the plasma concentration of flutamide maintained at a high level and OH-flutamide stayed low; a higher amount of FLU-1, an alternative metabolite of flutamide, was detected in urine. Simple repetitive administration of 800 mg/kg of flutamide for 28 days to CYP1A2 knockout mice did not show abnormal elevation of plasma alanine aminotransferase (ALT). However, after the knockout mice were fed with an amino acid-deficient diet for 2 weeks, which reduced the glutathione (GSH) content to 27% of the initial, administration of 400 mg/kg of flutamide increased ALT to over 200 IU/l and histopathologically moderate hepatitis developed. Since FLU-1 itself did not show cytotoxicity or reduce GSH content in vitro, a further metabolized molecule must cause the hepatotoxicity.
Blockade of CYP1A2 produced an unknown potential hepatotoxic molecule through FLU-1, and GSH might play an important role in diminishing the reactive hepatotoxic metabolite.
氟他胺是一种用于治疗前列腺癌的非甾体类抗雄激素药物，可导致转氨酶暂时升高，在某些情况下还会引起严重的肝功能障碍。它主要通过细胞色素P450（CYP）1A2代谢为2-羟基氟他胺（OH-氟他胺），后者具有更强的抗雄激素活性，对培养的肝细胞无明显细胞毒性。我们推测可能是另一种次要代谢产物导致了肝毒性。
每天给CYP1A2基因敲除小鼠和野生型SV129小鼠施用氟他胺，以比较药代动力学和肝毒性表现。
在CYP1A2基因敲除小鼠中，氟他胺的血浆浓度维持在高水平，而OH-氟他胺水平较低；在尿液中检测到较高量的氟他胺替代代谢产物FLU-1。对CYP1A2基因敲除小鼠简单重复施用800mg/kg氟他胺28天，未显示血浆丙氨酸转氨酶（ALT）异常升高。然而，在基因敲除小鼠喂食缺乏氨基酸的饮食2周后，其谷胱甘肽（GSH）含量降至初始水平的27%，施用400mg/kg氟他胺后ALT升高至超过200IU/l，并且组织病理学显示出现中度肝炎。由于FLU-1本身在体外未显示细胞毒性或降低GSH含量，因此必定是进一步代谢的分子导致了肝毒性。
CYP1A2的阻断通过FLU-1产生了一种未知的潜在肝毒性分子，GSH可能在减少活性肝毒性代谢产物方面发挥重要作用。
