Advanced

N,N'-Bis(2-mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol-Induced Liver Toxicity

Nilsson, Johan L.Å. LU ; Blomgren, Anders LU ; Nilsson, Ulf J. LU ; Högestätt, Edward D. LU and Grundemar, Lars LU (2018) In Basic and Clinical Pharmacology and Toxicology2004-01-01+01:002014-01-01+01:00 123(5). p.589-593
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Basic and Clinical Pharmacology and Toxicology2004-01-01+01:002014-01-01+01:00
volume
123
issue
5
pages
589 - 593
publisher
Wiley-Blackwell
external identifiers
  • scopus:85050650109
ISSN
1742-7835
DOI
10.1111/bcpt.13058
language
English
LU publication?
yes
id
133c0b8a-832f-4c2a-bed3-10ea29d9cac1
date added to LUP
2018-09-24 14:50:02
date last changed
2019-01-14 16:31:17
@article{133c0b8a-832f-4c2a-bed3-10ea29d9cac1,
  abstract     = {<p>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.</p>},
  author       = {Nilsson, Johan L.Å. and Blomgren, Anders and Nilsson, Ulf J. and Högestätt, Edward D. and Grundemar, Lars},
  issn         = {1742-7835},
  language     = {eng},
  month        = {06},
  number       = {5},
  pages        = {589--593},
  publisher    = {Wiley-Blackwell},
  series       = {Basic and Clinical Pharmacology and Toxicology2004-01-01+01:002014-01-01+01:00},
  title        = {N,N'-Bis(2-mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol-Induced Liver Toxicity},
  url          = {http://dx.doi.org/10.1111/bcpt.13058},
  volume       = {123},
  year         = {2018},
}