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 M 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

Research output: Contribution to journalArticle

66 Citations (Scopus)

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

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Isoniazid
Liver Failure
Cytochrome P-450 CYP2E1
Cytochrome P-450 Enzyme System
Anti-Idiotypic Antibodies
Chemical and Drug Induced Liver Injury
Cytochrome P-450 CYP3A
Antibodies
Liver
Wounds and Injuries
Serum
Gastroenterology
Exanthema
Fever
Cytochrome P-450 CYP2C9

ASJC Scopus subject areas

  • Hepatology

Cite this

Metushi, I. G., Sanders, C., Lee, W. M., Larson, A. M., Liou, I., Davern, 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

Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure. / Metushi, Imir G.; Sanders, Corron; Lee, W. M.; Larson, Anne M.; Liou, Iris; Davern, Timothy; Fix, Oren; Schilsky, Michael; McCashland, Timothy M; Hay, J. Eileen; Murray, Natalie; Shaikh, A. Obaid S; Blei, Andres; Ganger, Daniel; Zaman, Atif; Han, Steven H B; Fontana, Robert; McGuire, Brendan; Chung, Raymond T.; Smith, Alastair; Brown, Robert; Crippin, Jeffrey; Harrison, Edwin; Reuben, Adrian; Munoz, Santiago; Reddy, Rajender; Stravitz, R. Todd; Rossaro, Lorenzo; Satyanarayana, Raj; Hassanein, Tarek; Samuel, Grace; Lalani, Ezmina; Pezzia, Carla; Attar, Nahid; Hynan, Linda S.; Durkalski, Valerie; Zhao, Wenle; Dillon, Catherine; Battenhouse, Holly; Goddard, Tomoko; Lee, William M.; Uetrecht, Jack.

In: Hepatology, Vol. 59, No. 3, 01.03.2014, p. 1084-1093.

Research output: Contribution to journalArticle

Metushi, IG, Sanders, C, Lee, WM, Larson, AM, Liou, I, Davern, T, Fix, O, Schilsky, M, McCashland, TM, Hay, JE, Murray, N, Shaikh, AOS, Blei, A, Ganger, D, Zaman, A, Han, SHB, Fontana, R, McGuire, B, Chung, RT, Smith, A, Brown, R, Crippin, J, Harrison, E, Reuben, A, Munoz, S, Reddy, R, Stravitz, RT, Rossaro, L, Satyanarayana, R, Hassanein, T, Samuel, G, Lalani, E, Pezzia, C, Attar, N, Hynan, LS, Durkalski, V, Zhao, W, Dillon, C, Battenhouse, H, Goddard, T, Lee, WM & Uetrecht, J 2014, 'Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure', Hepatology, vol. 59, no. 3, pp. 1084-1093. https://doi.org/10.1002/hep.26564
Metushi, Imir G. ; Sanders, Corron ; Lee, W. M. ; Larson, Anne M. ; Liou, Iris ; Davern, Timothy ; Fix, Oren ; Schilsky, Michael ; McCashland, Timothy M ; Hay, J. Eileen ; Murray, Natalie ; Shaikh, A. Obaid S ; Blei, Andres ; Ganger, Daniel ; Zaman, Atif ; Han, Steven H B ; Fontana, Robert ; McGuire, Brendan ; Chung, Raymond T. ; Smith, Alastair ; Brown, Robert ; Crippin, Jeffrey ; Harrison, Edwin ; Reuben, Adrian ; Munoz, Santiago ; Reddy, Rajender ; Stravitz, R. Todd ; Rossaro, Lorenzo ; Satyanarayana, Raj ; Hassanein, Tarek ; Samuel, Grace ; Lalani, Ezmina ; Pezzia, Carla ; Attar, Nahid ; Hynan, Linda S. ; Durkalski, Valerie ; Zhao, Wenle ; Dillon, Catherine ; Battenhouse, Holly ; Goddard, Tomoko ; Lee, William M. ; Uetrecht, Jack. / Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure. In: Hepatology. 2014 ; Vol. 59, No. 3. pp. 1084-1093.
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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)",
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T1 - Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure

AU - Metushi, Imir G.

AU - Sanders, Corron

AU - Lee, W. M.

AU - Larson, Anne M.

AU - Liou, Iris

AU - Davern, Timothy

AU - Fix, Oren

AU - Schilsky, Michael

AU - McCashland, Timothy M

AU - Hay, J. Eileen

AU - Murray, Natalie

AU - Shaikh, A. Obaid S

AU - Blei, Andres

AU - Ganger, Daniel

AU - Zaman, Atif

AU - Han, Steven H B

AU - Fontana, Robert

AU - McGuire, Brendan

AU - Chung, Raymond T.

AU - Smith, Alastair

AU - Brown, Robert

AU - Crippin, Jeffrey

AU - Harrison, Edwin

AU - Reuben, Adrian

AU - Munoz, Santiago

AU - Reddy, Rajender

AU - Stravitz, R. Todd

AU - Rossaro, Lorenzo

AU - Satyanarayana, Raj

AU - Hassanein, Tarek

AU - Samuel, Grace

AU - Lalani, Ezmina

AU - Pezzia, Carla

AU - Attar, Nahid

AU - Hynan, Linda S.

AU - Durkalski, Valerie

AU - Zhao, Wenle

AU - Dillon, Catherine

AU - Battenhouse, Holly

AU - Goddard, Tomoko

AU - Lee, William M.

AU - Uetrecht, Jack

PY - 2014/3/1

Y1 - 2014/3/1

N2 - 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)

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