thioacetamide and 2-aminoethoxydiphenyl-borate

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.

Topics: Acetaminophen; Animals; Boron Compounds; Chemical and Drug Induced Liver Injury; Connexins; Gap Junction beta-1 Protein; Gap Junctions; HeLa Cells; Humans; Liver Failure, Acute; Mice; Mice, Inbred C57BL; Protective Agents; Thioacetamide