Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2+/- mice
Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2+/- mice
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DOI：
10.1016/j.freeradbiomed.2005.08.038
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发表时间：
2006-02-01
影响因子：
7.4
通讯作者：
Boelsterli, UA
中科院分区：
文献类型：
--
作者：
Ong, MMK;Wang, AS;Boelsterli, UA
尼美舒利是一种优先的COX-2抑制剂，与罕见的特异性肝毒性有关。肝损伤的潜在机制尚不清楚，但实验证据已经确定氧化应激是一个潜在的危险，线粒体是一个目标。本研究的目的是探讨遗传线粒体异常是否会导致线粒体功能受损和轻度氧化应激增加，从而使小鼠对尼美舒利的肝脏不良反应敏感。我们使用杂合子超氧化物歧化酶2（Sod2(+/-)）小鼠作为模型，因为这些小鼠出现临床沉默的线粒体应激，但其他方面表现正常。尼美舒利给药4周（10mg / kg, ip, bid），剂量相当于人体治疗剂量。我们发现该药物增强了Sod2（+/-）小鼠肝脏线粒体氧化损伤（降低乌头酶活性，增加蛋白质羰基），但对野生型小鼠没有作用。此外，尼美舒利处理的突变小鼠表现出增加的肝细胞质细胞色素c和caspase-3活性水平，以及增加的凋亡肝细胞数量。最后，尼美舒利在体外引起Sod2（+/-）小鼠线粒体中超氧阴离子的浓度依赖性净增加，而Sot2（+/+）小鼠则没有。综上所述，尼美舒利可在线粒体功能受损的小鼠中叠加氧化应激，增强线粒体损伤，并激活促凋亡因子。(c) 2005爱思唯尔公司版权所有。
Nimesulide, a preferential COX-2 inhibitor, has been associated with rare idiosyncratic hepatotoxicity. The underlying mechanisms of liver injury are unknown, but experimental evidence has identified oxidative stress as a potential hazard and mitochondria as a target. The aim of this study was to explore whether genetic mitochondrial abnormalities, resulting in impaired mitochondrial function and mildly increased oxidative stress, might sensitize mice to the hepatic adverse effects of nimesulide. We used heterozygous superoxide dismutase 2 (Sod2(+/-)) mice as a model, as these mice develop clinically silent mitochondrial stress but otherwise appear normal. Nimesulide was administered for 4 weeks (10 mg/ kg, ip, bid), at a dose equivalent to human therapeutic dosage. We found that the drug potentiated hepatic mitochondrial oxidative injury (decreased aconitase activity, increased protein carbonyls) in Sod2(+/-), but not wild-type, mice. Furthermore, the nimesulide-treated mutant mice exhibited increased hepatic cytosolic levels of cytochrome c and caspase-3 activity, as well as increased numbers of apoptotic hepatocytes. Finally, nimesulide in vitro caused a concentration-dependent net increase in superoxide anion in mitochondria from Sod2(+/-), but not Sot2(+/+) mice. In conclusion, repeated administration of nimesulide can superimpose an oxidant stress, potentiate mitochondrial damage, and activate proapoptotic factors in mice with genetically compromised mitochondrial function. (c) 2005 Elsevier Inc. All rights reserved.