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

Suraj J. Patel, Jack M. Milwid, Kevin R. King, Stefan Bohr, Arvin Iracheta-Velle, Matthew Li, Antonia Vitalo, Biju Parekkadan, Rohit Jindal, Martin L. Yarmush

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine1,2. 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.

Original languageEnglish (US)
Pages (from-to)179-183
Number of pages5
JournalNature biotechnology
Issue number2
StatePublished - Feb 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering


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