N,N'-Bis(2-mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol-Induced Liver Toxicity
(2018) In Basic and Clinical Pharmacology and Toxicology 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.
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- author
- Nilsson, Johan L.Å. LU ; Blomgren, Anders LU ; Nilsson, Ulf J. LU ; Högestätt, Edward D. LU and Grundemar, Lars LU
- organization
- publishing date
- 2018-06-16
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Basic and Clinical Pharmacology and Toxicology
- volume
- 123
- issue
- 5
- pages
- 589 - 593
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:85050650109
- pmid:29908097
- 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
- 2024-09-03 01:32:20
@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 Toxicology}}, 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}}, doi = {{10.1111/bcpt.13058}}, volume = {{123}}, year = {{2018}}, }