Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury.
Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury.
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DOI：
10.1016/j.taap.2015.03.019
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发表时间：
2015-07-01
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Xie, Yuchao;Ramachandran, Anup;Breckenridge, David G.;Liles, John T.;Lebofsky, Margitta;Farhood, Anwar;Jaeschke, Hartmut
Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affected the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients.
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影响因子：
3.8
作者：
Du, Kuo;Williams, C. David;McGill, Mitchell R.;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut
影响因子：
4.1
作者：
Hinson, JA;Pike, SL;Mayeux, PR
通讯作者：
Mayeux, PR
影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
6
作者：
Bhushan, Bharat;Borude, Prachi;Apte, Udayan
通讯作者：
Apte, Udayan
影响因子：
13.5
作者：
Kon, K;Kim, JS;Lemasters, JJ
通讯作者：
Lemasters, JJ