title: Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure.
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.
  
  
  CONCLUSIONS
  These data provide strong evidence that INH induces an immune response that causes INH-induced liver injury.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Imir G
authors.initials: IG
authors.lastname: Metushi
authors.forename: Corron
authors.initials: C
authors.lastname: Sanders
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000995:Antitubercular Agents / Q000009:adverse effects / Q000276:immunology; D001189:Aryl Hydrocarbon Hydroxylases / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000276:immunology*; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology*; D051544:Cytochrome P-450 CYP3A / Q000276:immunology*; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000276:immunology; D017093:Liver Failure / Q000453:epidemiology / Q000276:immunology; D008297:Male; D008862:Microsomes, Liver / Q000276:immunology; D008875:Middle Aged; D012307:Risk Factors; D016036:Seroepidemiologic Studies; D055815:Young Adult
chemical_list: D000906:Antibodies; D000995:Antitubercular Agents; D001323:Autoantibodies; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007538:Isoniazid