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N,N ’‐Bis(2‐mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol‐Induced Liver Toxicity
Author(s) -
Nilsson Johan L. Å.,
Blomgren Anders,
Nilsson Ulf J.,
Högestätt Edward D.,
Grundemar Lars
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13058
Subject(s) - liver injury , acetaminophen , pharmacology , toxicity , chemistry , antidote , fulminant hepatic failure , acetylcysteine , medicine , biochemistry , liver transplantation , organic chemistry , transplantation , antioxidant
Paracetamol overdosing may cause liver injury including fulminant liver failure due to generation of the toxic metabolites, N ‐acetyl‐p‐benzoquinone imine ( NAPQI ) and p‐benzoquinone (p‐ BQ ). Herein, the chelating agent, N,N ’‐Bis(2‐mercaptoethyl)isophthalamide ( NBMI ), was examined for its potential ability to entrap NAPQI and p‐ BQ and to prevent paracetamol‐induced liver injury. Both NBMI and the conventional paracetamol antidote N ‐acetylcysteine ( NAC ) were investigated with regard to their abilities to scavenge the NAPQI and p‐ BQ in a Transient Receptor Potential Ankyrin 1‐dependent screening assay. Stoichiometric evaluations indicated that NBMI was able to entrap these metabolites more efficiently than NAC . Furthermore, oral administration of either NBMI (680 mg/kg) or NAC (680 mg/kg) prevented the development of the characteristic liver necrosis and elevation of serum alanine aminotransferase in a mouse model for paracetamol‐induced liver injury. In summary, these results show that NBMI is able to entrap the toxic metabolites NAPQI and p‐ BQ and to prevent paracetamol‐induced liver injury in mice.