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

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.

• Authors: Suraj J Patel, Jack M Milwid, Kevin R King, Stefan Bohr, Arvin Iracheta-Vellve, Arvin Iracheta-Velle, Matthew Li, Antonia Vitalo, Biju Parekkadan, Rohit Jindal, Martin L Yarmush
• Journal: Nature biotechnology (Nat Biotechnol) Vol. 30 Issue 2 Pg. 179-83 (Jan 15 2012) ISSN: 1546-1696 [Electronic] United States
• PMID: 22252509 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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