Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury -: Roles of cytochrome c, Bax, Bid, and caspases
Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury -: Roles of cytochrome c, Bax, Bid, and caspases
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DOI：
10.1016/s0041-008x(03)00240-0
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发表时间：
2003-09-01
影响因子：
3.8
通讯作者：
Kass, GEN
中科院分区：
文献类型：
--
作者：
El-Hassan, H;Anwar, K;Kass, GEN
研究了细胞凋亡在对乙酰氨基酚（AAP）诱导的肝损伤中的作用。在给BALB/c小鼠AAP 6小时后，观察到肝脏线粒体细胞色素c的显著丢失，其程度与通过抗体处理激活CD95后观察到的损失相似。aap诱导的线粒体细胞色素c的丢失与截断的Bid （tBid）对应的片段在细胞质中出现一致。同时，在线粒体部分检测到tBid，同时发现Bax易位到线粒体。然而，AAP未能激活执行caspase 3和7，这可以通过缺乏procaspase加工和caspase-3样活性没有增加来证明。相比之下，半胱天冬酶泛抑制剂benzyloxycarbonyl- val - ala - dl - asp -氟甲基酮（而不是其类似物benzyloxycarbonyl- ph - ala -氟甲基酮）的使用阻止了AAP肝损伤的发展和实质细胞凋亡的出现。这与抑制Bid到tBid的加工有关。caspase抑制剂未能阻止Bax向线粒体的重新分布和细胞色素c的丢失。综上所述，细胞凋亡是AAP引起肝损伤的一个重要原因。然而，由于缺乏主要执行半胱天冬酶的激活，细胞凋亡不能正常执行并退化为坏死。(C) 2003 Elsevier Inc.版权所有。
The role of apoptosis in acetaminophen (AAP)-induced hepatic injury was investigated. Six hours after AAP administration to BALB/c mice, a significant loss of hepatic mitochondrial cytochrome c was observed that was similar in extent to the loss observed after in vivo activation of CD95 by antibody treatment. AAP-induced loss of mitochondrial cytochrome c coincided with the appearance in the cytosol of a fragment corresponding to truncated Bid (tBid). At the same time, tBid became detectable in the mitochondrial fraction, and concomitantly, Bax was found translocated to mitochondria. However, AAP failed to activate the execution caspases 3 and 7 as evidenced by a lack of procaspase processing and the absence of an increase in caspase-3-like activity. In contrast, the administration of the pan-inhibitor of caspases, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (but not its analogue benzyloxycarbonyl-Phe-Ala-fluoromethylketone) prevented the development of liver injury by AAP and the appearance of apoptotic parenchymal cells. This correlated with the inhibition of the processing of Bid to tBid. The caspase inhibitor failed to prevent both the redistribution of Bax to the mitochondria and the loss of cytochrome c. In conclusion, apoptosis is an important causal event in the initiation of the hepatic injury inflicted by AAP. However, as suggested by the lack of activation of the main execution caspases, apoptosis is not properly executed and degenerates into necrosis. (C) 2003 Elsevier Inc. All rights reserved.