Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure

Imir G. Metushi, Corron Sanders, W. M. Lee, Anne M. Larson, Iris Liou, Timothy Davern, Oren Fix, Michael Schilsky, Timothy McCashland, J. Eileen Hay, Natalie Murray, A. Obaid S. Shaikh, Andres Blei, Daniel Ganger, Atif Zaman, Steven H.B. Han, Robert Fontana, Brendan McGuire, Raymond T. Chung, Alastair SmithRobert Brown, Jeffrey Crippin, Edwin Harrison, Adrian Reuben, Santiago Munoz, Rajender Reddy, R. Todd Stravitz, Lorenzo Rossaro, Raj Satyanarayana, Tarek Hassanein, Grace Samuel, Ezmina Lalani, Carla Pezzia, Nahid Attar, Linda S. Hynan, Valerie Durkalski, Wenle Zhao, Catherine Dillon, Holly Battenhouse, Tomoko Goddard, William M. Lee, Jack Uetrecht*

*Corresponding author for this work

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Isoniazid (INH)-induced hepatotoxicity remains one of the most common causes of drug-induced idiosyncratic liver injury and liver failure. This form of liver injury is not believed to be immune-mediated because it is not usually associated with fever or rash, does not recur more rapidly on rechallenge, and previous studies have failed to identify anti-INH antibodies (Abs). In this study, we found Abs present in sera of 15 of 19 cases of INH-induced liver failure. Anti-INH Abs were present in 8 sera; 11 had anti-cytochrome P450 (CYP)2E1 Abs, 14 had Abs against CYP2E1 modified by INH, 14 had anti-CYP3A4 antibodies, and 10 had anti-CYP2C9 Abs. INH was found to form covalent adducts with CYP2E1, CYP3A4, and CYP2C9. None of these Abs were detected in sera from INH-treated controls without significant liver injury. The presence of a range of antidrug and autoAbs has been observed in other drug-induced liver injury that is presumed to be immune mediated. Conclusion: These data provide strong evidence that INH induces an immune response that causes INH-induced liver injury. (Hepatology 2014;59:1084-1093)

Original languageEnglish (US)
Pages (from-to)1084-1093
Number of pages10
JournalHepatology
Volume59
Issue number3
DOIs
StatePublished - Mar 1 2014

ASJC Scopus subject areas

  • Hepatology

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    Metushi, I. G., Sanders, C., Lee, W. M., Larson, A. M., Liou, I., Davern, T., Fix, O., Schilsky, M., McCashland, T., Hay, J. E., Murray, N., Shaikh, A. O. S., Blei, A., Ganger, D., Zaman, A., Han, S. H. B., Fontana, R., McGuire, B., Chung, R. T., ... Uetrecht, J. (2014). Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure. Hepatology, 59(3), 1084-1093. https://doi.org/10.1002/hep.26564