title: 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.affiliation: Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Suraj J
authors.initials: SJ
authors.lastname: Patel
authors.forename: Jack M
authors.initials: JM
authors.lastname: Milwid
authors.forename: Kevin R
authors.initials: KR
authors.lastname: King
authors.forename: Stefan
authors.initials: S
authors.lastname: Bohr
authors.forename: Arvin
authors.initials: A
authors.lastname: Iracheta-Vellve
authors.forename: Arvin
authors.initials: A
authors.lastname: Iracheta-Velle
authors.forename: Matthew
authors.initials: M
authors.lastname: Li
authors.forename: Antonia
authors.initials: A
authors.lastname: Vitalo
authors.forename: Biju
authors.initials: B
authors.lastname: Parekkadan
authors.forename: Rohit
authors.initials: R
authors.lastname: Jindal
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000008:administration & dosage*; D013853:Thioacetamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000097002:Gap Junction beta-1 Protein
chemical_list: D000082:Acetaminophen; D001896:Boron Compounds; D017630:Connexins; D020011:Protective Agents; D013853:Thioacetamide; D000097002:Gap Junction beta-1 Protein; C029188:thioacetamide-S-oxide; C109986:2-aminoethoxydiphenyl borate