title: Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin.
abstract: Isoniazid (INH), a widely used antituberculosis drug, has been associated with serious drug-induced liver injury (DILI). INH-modified proteins have been proposed to play important roles in INH DILI; however, it remains to be determined whether INH or reactive metabolites bind irreversibly to proteins. In this study, mass spectrometry was used to define protein modifications by INH in vitro and in patients taking INH therapy. When INH was incubated with N-acetyl lysine (NAL), the same isonicotinic-NAL (IN-NAL) adducts were detected irrespective of the presence or absence of any oxidative enzymes, indicating auto-oxidation may have been involved. In addition, we found that INH could also bind to human serum albumin (HSA) via an auto-oxidation pathway, forming isonicotinic amide adducts with lysine residues in HSA. Similar adducts were detected in plasma samples isolated from patients taking INH therapy. Our results show that INH forms protein adducts in the absence of metabolism.
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE, United Kingdom.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Meng
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE, United Kingdom.
authors.forename: James L
authors.initials: JL
authors.lastname: Maggs
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE, United Kingdom.
authors.forename: Toru
authors.initials: T
authors.lastname: Usui
authors.affiliation: The Department of Respiratory Medicine, St. James's Hospital , Leeds LS9 7TF, West Yorkshire, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Whitaker
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE, United Kingdom.
authors.forename: Neil S
authors.initials: NS
authors.lastname: French
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE, United Kingdom.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE, United Kingdom.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D012709:Serum Albumin; D009249:NADP; D008239:Lysine; D007538:Isoniazid