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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetaminophen / adverse effects*
  • Acetaminophen / analogs & derivatives
  • Acetaminophen / therapeutic use
  • Animals
  • Boron Compounds / administration & dosage*
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / prevention & control
  • Connexins / antagonists & inhibitors*
  • Connexins / deficiency
  • Connexins / metabolism*
  • Gap Junctions / drug effects*
  • Gap Junctions / metabolism*
  • HeLa Cells
  • Humans
  • Liver Failure, Acute / chemically induced
  • Liver Failure, Acute / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Protective Agents / administration & dosage*
  • Thioacetamide / administration & dosage
  • Thioacetamide / adverse effects
  • Thioacetamide / analogs & derivatives

Substances

  • Boron Compounds
  • Connexins
  • Protective Agents
  • connexin 32
  • Thioacetamide
  • thioacetamide-S-oxide
  • Acetaminophen
  • 2-aminoethoxydiphenyl borate