Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity
Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity
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DOI：
10.1016/j.taap.2009.05.007
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发表时间：
2009-07-15
影响因子：
3.8
通讯作者：
Boelsterli, Urs A.
中科院分区：
文献类型：
--
作者：
Kashimshetty, Rohini;Desai, Varsha G.;Boelsterli, Urs A.
氟他胺是一种广泛使用的非甾体抗雄激素药物，但与其生物等排体比卡鲁胺无关，它与特殊药物引起的肝损伤有关。尽管易感因素尚不清楚，但线粒体损伤已成为氟他胺的假定危害。为了探讨线粒体致敏在氟他胺肝毒性中的作用，我们确定了潜在线粒体异常小鼠模型中叠加药物应激的影响。雄性野生型或杂合Sod2(+/-)小鼠腹腔注射氟他胺（0、30或100mg/kg/天），持续28天。一项动力学初步研究表明，氟他胺（100 毫克/公斤/天）造成的暴露量比报告的治疗平均血浆水平高约 10 倍。高剂量组中的突变型（5/10）小鼠（而非野生型小鼠）表现出小肝细胞坏死灶和凋亡肝细胞数量增加。肝脏 GSSG/GSH、蛋白质羰基水平和血清乳酸水平显着升高，表明氧化应激和线粒体功能障碍。对培养的肝细胞中线粒体超氧化物的测量表明，线粒体是氟他胺增强的氧化应激的重要来源。事实上，与载体对照相比，从氟他胺治疗的 Sod2(+/-) 小鼠中分离的线粒体表现出乌头酸酶活性降低。使用 MitoChips 进行的转录组学分析显示，氟他胺治疗的 Sod2(+/-) 小鼠的线粒体 DNA 编码的所有复合物 I 和 III 亚基的表达选择性降低。相比之下，接受比卡鲁胺（50 mg/kg/天）的 Sod2(+/-) 小鼠没有表现出任何肝脏变化。这些结果与我们的概念相一致，即氟他胺靶向肝线粒体并施加氧化应激，在存在潜在线粒体异常的情况下可能导致明显的肝损伤。 (C) 2009 Elsevier Inc. 保留所有权利。
Flutamide, a widely used nonsteroidal anti-androgen, but not its bioisostere bicalutamide, has been associated with idiosyncratic drug-induced liver injury. Although the susceptibility factors are unknown, mitochondrial injury has emerged as a putative hazard of flutamide. To explore the role of mitochondrial sensitization in flutamide hepatotoxicity, we determined the effects of superimposed drug stress in a murine model of underlying mitochondrial abnormalities. Male wild-type or heterozygous Sod2(+/-) mice were injected intraperitoneously with flutamide (0, 30 or 100 mg/kg/day) for 28 days. A kinetic pilot study revealed that flutamide (100 mg/kg/day) caused approximately 10-fold greater exposure than the reported therapeutic mean plasma levels. Mutant (5/10), but not wild-type, mice in the high-dose group exhibited small foci of hepatocellular necrosis and an increased number of apoptotic hepatocytes. Hepatic GSSG/GSH, protein carbonyl levels, and serum lactate levels were significantly increased, suggesting oxidant stress and mitochondrial dysfunction. Measurement of mitochondrial superoxide in cultured hepatocytes demonstrated that mitochondria were a significant source of flutamide-enhanced oxidant stress. Indeed, mitochondria isolated from flutamide-treated Sod2(+/-) mice exhibited decreased aconitase activity as compared to vehicle controls. A transcriptomics analysis using MitoChips revealed that flutamide-treated Sod2(+/-) mice exhibited a selective decrease in the expression of all complexes I and III subunits encoded by mitochondrial DNA. In contrast, Sod2(+/-) mice receiving bicalutamide (50 mg/kg/day) did not reveal any hepatic changes. These results are compatible with our concept that flutamide targets hepatic mitochondria and exerts oxidant stress that can lead to overt hepatic injury in the presence of an underlying mitochondrial abnormality. (C) 2009 Elsevier Inc. All rights reserved.