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Nat Biotechnol. 2012 Jan 15;30(2):179-83. doi: 10.1038/nbt.2089.

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

Author information

1
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

Erratum in

  • Nat Biotechnol. 2014 Mar;32(3):291. Iracheta-Velle, Arvin [corrected to Iracheta-Vellve, Arvin].

Abstract

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. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are 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 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.

PMID:
22252509
PMCID:
PMC3609650
DOI:
10.1038/nbt.2089
[Indexed for MEDLINE]
Free PMC Article

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