Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure

作者：Patel Suraj J; Milwid Jack M; King Kevin R; Bohr Stefan; Iracheta Velle Arvin; Li Matthew; Vitalo Antonia; Parekkadan Biju; Jindal Rohit; Yarmush Martin L^*

来源：Nature Biotechnology, 2012, 30(2): 179-183.

DOI：10.1038/nbt.2089

Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine(1,2). Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI3. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate 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 caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety.

• 出版日期2012-2