Mechanisms of drug-induced liver injury.
Mechanisms of drug-induced liver injury.
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DOI：
10.1016/j.cld.2013.07.002
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发表时间：
2013-11
影响因子：
5.1
通讯作者：
Kaplowitz N
中科院分区：
文献类型：
--
作者：
Yuan L;Kaplowitz N
药物性肝损伤（DILI）代表了广泛的肝脏表现。然而，最常见的表现是服药后肝细胞死亡。 DILI 是可预测的且具有剂量依赖性，其中以对乙酰氨基酚毒性为例。特殊性 DILI 以不可预测的方式低频率发生，这意味着环境和遗传因素改变了个体对伤害（药物）的易感性。生化应激通常由药物及其反应性代谢产物通过共价结合或直接损伤线粒体而引发，导致氧化应激、应激信号通路激活、线粒体功能损伤、内质网应激等。最终的细胞死亡途径通过作用于线粒体外膜通透性（MOMP）或线粒体通透性转变（MPT）而汇聚于线粒体。 HLA 与特异质 DILI 的显着关联凸显了适应性免疫反应在发病机制中的关键作用，现在认为在遗传易感个体中，药物和/或代谢物引发的肝脏生化应激揭示了这种作用。药物引起的生化应激也可能通过使肝细胞对免疫反应的致命效应敏感而导致损伤的严重程度。适应性机制包括抗氧化信号传导（例如 Nrf2 信号传导）、线粒体自噬、自噬、未折叠蛋白反应、抗炎和免疫耐受，可抑制和改善损伤。总而言之，损伤的发展和严重程度取决于肝细胞内的危险应激和适应性反应以及先天性和适应性免疫系统之间的斗争。
Drug induced liver injury (DILI) represents a broad spectrum of liver manifestations. However, the most common manifestation is hepatocyte death following drug intake. DILI can be predictable and dose dependent with notable example of acetaminophen toxicity. Idiosyncratic DILI occurs in an unpredictable fashion at low frequencies implying that environmental and genetic factors alter the susceptibility of individuals to the insult (drugs). An biochemical stress is usually initiated by drugs and their reactive metabolites through covalent binding or direct damage to mitochondria, which leads to oxidative stress, activation of stress signaling pathways, impairment of mitochondrial function, endoplasmic reticulum stress, etc. The ultimate cell death pathways converges at mitochondria through acting on mitochondrial outer-membrane permeability (MOMP) or mitochondrial permeability transition (MPT). The striking HLA associations with idiosyncratic DILI highlight the critical role of the adaptive immune response in pathogenesis, which is now believed to be unmasked in genetically susceptible individuals by the biochemical stress in the liver triggered by drug and/or metabolites. The drug-induced biochemical stress may also contribute to the severity of injury by sensitizing hepatocytes to the lethal effects of the immune response. Adaptive mechanisms including antioxidant signaling (such as Nrf2 signaling) , mitophagy, autophagy, unfolded protein response, anti-inflammatory and immune tolerance dampen and ameliorate injury. All together, the development and severity of injury is determined on the battle between the hazardous stress and adaptive responses within the hepatocytes and the innate and adaptive immune systems.
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影响因子：
--
作者：
Holt, Michael;Ju, Cynthia
通讯作者：
Ju, Cynthia
DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
影响因子：
3.8
作者：
Kashimshetty, Rohini;Desai, Varsha G.;Boelsterli, Urs A.
通讯作者：
Boelsterli, Urs A.
NRF2：氧化应激中的INRF2（KEAP1）信号传导。
影响因子：
7.4
作者：
Kaspar, James W.;Niture, Suryakant K.;Jaiswal, Anil K.
通讯作者：
Jaiswal, Anil K.
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK