The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation.
The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation.
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间隙连接抑制剂2-氨基甲氧基 - 二苯基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基抗毒性通过抑制细胞色素P450酶和C-Jun N末端激酶激活。
DOI：
10.1016/j.taap.2013.09.010
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发表时间：
2013-12-15
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Du, Kuo;Williams, C. David;McGill, Mitchell R.;Xie, Yuchao;Farhood, Anwar;Vinken, Mathieu;Jaeschke, Hartmut
关键词：
Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the US. Although many aspects of the mechanism are known, recent publications suggest that gap junctions composed of connexin32 function as critical intercellular communication channels which transfer cytotoxic mediators into neighboring hepatocytes and aggravate liver injury. However, these studies did not consider off-target effects of reagents used in these experiments, especially the gap junction inhibitor 2-aminoethoxy-diphenyl-borate (2-APB). In order to assess the mechanisms of protection of 2-APB in vivo, male C56Bl/6 mice were treated with 400 mg/kg APAP to cause extensive liver injury. This injury was prevented when animals were co-treated with 20 mg/kg 2-APB and was attenuated when 2-APB was administered 1.5h after APAP. However, the protection was completely lost when 2-APB was given 4–6h after APAP. Measurement of protein adducts and c-jun-N-terminal kinase (JNK) activation indicated that 2-APB reduced both protein binding and JNK activation, which correlated with hepatoprotection. Although some of the protection was due to the solvent dimethyl sulfoxide (DMSO), in vitro experiments clearly demonstrated that 2-APB directly inhibits cytochrome P450 activities. In addition, JNK activation induced by phorone and tert-butylhydroperoxide in vivo was inhibited by 2-APB. The effects against APAP toxicity in vivo were reproduced in primary cultured hepatocytes without use of DMSO and in the absence of functional gap junctions. We conclude that the protective effect of 2-APB was caused by inhibition of metabolic activation of APAP and inhibition of the JNK signaling pathway and not by blocking connexin32-based gap junctions.
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影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Kon, K;Kim, JS;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
3.8
作者：
Bajt, ML;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
3.8
作者：
McGill, Mitchell R.;Lebofsky, Margitta;Norris, Hye-Ryun K.;Slawson, Matthew H.;Bajt, Mary Lynn;Xie, Yuchao;Williams, C. David;Wilkins, Diana G.;Rollins, Douglas E.;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut