Reduction of toxic metabolite formation of acetaminophen

Eszter Hazai, L. Vereczkey, K. Monostory

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Acetaminophen is a widely used over-the-counter drug that causes severe hepatic damage upon overdose. Cytochrome P450-dependent oxidation of acetaminophen results in the formation of the toxic N-acetyl-p-benzoquinone-imine (NAPQI). Inhibition of cytochrome P450 enzymes responsible for NAPQI formation might be useful- besides N-acetylcysteine treatment- in managing acetaminophen overdose. Investigations were carried out using human liver microsomes to test whether selective inhibition of cytochrome P450s reduces NAPQI formation. Selective inhibition of CYP3A4 and CYP1A2 did not reduce, whereas the inhibition of CYP2A6 and CYP2E1 significantly decreased NAPQI formation. Furthermore, selective CYP2E1 inhibitors that are used in human therapy were tested for their inhibitory effect on NAPQI formation. 4-Methylpyrazole, disulfiram, and diethyl-dithiocarbamate were the most potent inhibitors with IC50 values of 50 μM, 8 μM, and 33 μM, respectively. Although cimetidin is used in the therapy of acetaminophen overdose as an inhibitor of cytochrome P450, it is not able to reduce NAPQI formation.

Original languageEnglish
Pages (from-to)1089-1094
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume291
Issue number4
DOIs
Publication statusPublished - 2002

Fingerprint

Imines
Poisons
Acetaminophen
Metabolites
Cytochrome P-450 Enzyme System
Nonprescription Drugs
Disulfiram
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP1A2
Acetylcysteine
Liver Microsomes
Cytochromes
Liver
Inhibitory Concentration 50
benzoquinone
Oxidation
Therapeutics

Keywords

  • 4-Methylpyrazole
  • Acetaminophen
  • Cimetidine
  • CYP2E1
  • Diethyl-dithiocarbamate
  • Disulfiram
  • Enzyme inhibition
  • Human microsomes
  • N-acetyl-p-benzoquinone-imine

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Reduction of toxic metabolite formation of acetaminophen. / Hazai, Eszter; Vereczkey, L.; Monostory, K.

In: Biochemical and Biophysical Research Communications, Vol. 291, No. 4, 2002, p. 1089-1094.

Research output: Contribution to journalArticle

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