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

TY - JOUR

T1 - Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure

AU - Patel, Suraj J.

AU - Milwid, Jack M.

AU - King, Kevin R.

AU - Bohr, Stefan

AU - Iracheta-Velle, Arvin

AU - Li, Matthew

AU - Vitalo, Antonia

AU - Parekkadan, Biju

AU - Jindal, Rohit

AU - Yarmush, Martin L.

N1 - Funding Information: The authors thank K. Willecke (University of Bonn) and D. Paul (Harvard University) for the generous gift of Cx32−/− mice, K. Willecke (University of Bonn) for connexin expressing HeLa cells, H. Duffy (Harvard Medical School) for development of the tissue scrape-and-load assay, and M. Izamis (Harvard Medical School) for high-performance liquid chromatography assistance. S.J.P. was supported in part by a Department of Defense Congressionally Directed Medical Research Program Prostate Cancer Predoctoral Training Award and a Shriners Hospitals for Children Postdoctoral Fellowship Award. The work was supported by Funding Information: grants from the US National Institutes of Health (DK059766 and P41 EB-002503) and from the Shriners Hospitals for Children.

PY - 2012/2

Y1 - 2012/2

N2 - Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine1,2. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI3. 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.

AB - Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine1,2. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI3. 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.

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U2 - https://doi.org/10.1038/nbt.2089

DO - https://doi.org/10.1038/nbt.2089

M3 - Article

C2 - 22252509

SN - 0733-222X

VL - 30

SP - 179

EP - 183

JO - Bio/Technology

JF - Bio/Technology

IS - 2

ER -