Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.
Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.
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DOI：
10.1016/j.tips.2013.01.009
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发表时间：
2013-04
影响因子：
13.8
通讯作者：
Kaplowitz N
中科院分区：
文献类型：
--
作者：
Han D;Dara L;Win S;Than TA;Yuan L;Abbasi SQ;Liu ZX;Kaplowitz N
导致肝损伤的药物通常会“刺激”线粒体并激活决定细胞存活或死亡的重要信号转导途径。在大多数情况下，肝细胞通过激活适应性信号通路来适应药物诱导的应激，如线粒体适应性反应和红细胞2相关因子2 (Nrf-2)，一种上调抗氧化防御的转录因子。由于适应作用，药物本身很少引起肝损伤，对乙酰氨基酚是一个明显的例外。药物性肝损伤（DILI）通常涉及其他外在因素，如适应性免疫系统，导致“应激”肝细胞受损；导致特异性DILI，即肝脏罕见且不可预测的药物不良反应。肝细胞损伤，由于药物和外源性损伤，引起与适应、细胞死亡和修复相关的第二波信号变化。如果应激和损伤达到临界阈值，则JNK等死亡信号通路成为主导，肝细胞进入failsafe模式进行自我毁灭。DILI可以被视为一个主动的过程，涉及死亡信号通路的募集，介导细胞死亡，而不是一个被动的过程，由于压倒性的生化损伤。在这篇综述中，我们强调了信号转导途径的作用，其中经常涉及线粒体，在DILI的发展。
Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause “stressed” hepatocytes to become injured; leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as JNK become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI.
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