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

Nature Biotechnology volume 30, pages 179–183 (2012)Cite this article

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An Erratum to this article was published on 10 March 2014

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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 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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Figure 1: Chemically induced hepatotoxicity is dependent on connexin 32.
Figure 2: Small-molecule inhibitors of Cx32 selectively block hepatic gap junction communication and prevent drug-induced hepatotoxicity.
Figure 3: Co-administration of hepatotoxic compounds with Cx32 inhibitors reduces liver injury, limits inflammation, and enhances survival.

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  • 05 December 2013

    In the version of this article initially published, Arvin Iracheta-Vellve's name was incorrectly spelled as Arvin Iracheta-Velle. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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 grants from the US National Institutes of Health (DK059766 and P41 EB-002503) and from the Shriners Hospitals for Children.

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Authors and Affiliations

  1. Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, and the Shriners Burns Hospital, Boston, Massachusetts, USA

    Suraj J Patel, Jack M Milwid, Kevin R King, Stefan Bohr, Arvin Iracheta-Vellve, Matthew Li, Antonia Vitalo, Biju Parekkadan, Rohit Jindal & Martin L Yarmush

  2. Harvard-MIT Division of Health Science and Technology, Harvard Medical School, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Suraj J Patel, Jack M Milwid & Martin L Yarmush

  3. Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA

    Rohit Jindal & Martin L Yarmush

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Contributions

S.J.P. initiated the project, performed the experiments, analyzed data and wrote the manuscript. J.M.M. and K.R.K. performed the experiments, provided experimental advice and wrote the manuscript. S.B., M.L., A.I.-V. and A.V. performed the experiments and analyzed data. R.J. and B.P. provided conceptual and editorial support. M.L.Y. supervised the project.

Corresponding author

Correspondence to Martin L Yarmush.

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Competing interests

S.J.P., J.M.M., K.R.K. and M.L.Y. are inventors on a patent application, and S.J.P., K.R.K. and M.L.Y. hold founder's equity in a company pertaining to the technology described in this paper.

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Patel, S., Milwid, J., King, K. et al. Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. Nat Biotechnol 30, 179–183 (2012). https://doi.org/10.1038/nbt.2089

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