Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure.
Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure.
复制标题
DOI：
10.1038/nbt.2089
复制
发表时间：
2012-01-15
影响因子：
46.9
通讯作者：
中科院分区：
文献类型：
--
作者：
药物性肝损伤(DILI)限制了大量治疗药物的开发和利用，给制药工业和临床医学带来了重大挑战。含有对乙酰氨基酚(APAP)的化合物是最常见的处方药之一，也是导致DILI的最常见原因。在这里，我们描述了一种针对缝隙连接通讯的药理策略，以防止暴发性肝衰竭和APAP诱导的肝毒性的放大。我们报道了一种关键的肝脏缝隙连接蛋白Cx32(Cx32)，它是DILI的重要介质，因为Cx32基因缺陷的小鼠可以保护肝脏免受损伤、急性炎症和死亡。我们确定了一种Cx32的小分子抑制剂作为一种新的肝脏保护剂，当与已知的肝毒性药物联合使用时，在野生型小鼠身上取得了同样的结果。这些发现表明，缝隙连接抑制是一种有效的限制DILI的治疗方法，并为提高药物安全性提供了一种新的药物策略。
Drug-induced liver injury (DILI) limits the development and utilization of numerous therapeutic compounds, and consequently presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen (APAP) containing compounds are among the most frequently prescribed drugs, and also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and APAP-induced hepatotoxicity. We report that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation, and death. We identified a small molecule inhibitor of Cx32 as a novel hepatoprotectant that achieves the same result in wildtype mice when coadministered with known hepatotoxic drugs. These findings demonstrate that gap junction inhibition is an effective therapy for limiting DILI, and suggest a novel pharmaceutical strategy to improve drug safety.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
通讯作者：
Rock, Kenneth L.
影响因子：
3.8
作者：
Jaeschke, H;Gores, GJ;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
--
作者：
Wysowski, DK;Swartz, L
通讯作者：
Swartz, L
影响因子：
5.9
作者：
BIRNBAUM, J;KAHAN, FM;MACDONALD, JS
通讯作者：
MACDONALD, JS
影响因子：
29.4
作者：
Lee, William M.;Hynan, Linda S.;Robuck, Patricia R.
通讯作者：
Robuck, Patricia R.