Rat liver ADP-ribose pyrophosphatase-I as an in vitro target of the acetaminophen metabolite N-acetyl-p-benzoquinoneimine

Biochim Biophys Acta. 1997 Oct 20;1336(3):403-8. doi: 10.1016/s0304-4165(97)00051-2.

Abstract

N-acetyl-p-benzoquinoneimine (NAPQI) is the metabolite responsible for acetaminophen hepatotoxicity. ADP-ribose pyrophosphatase-I (ADPRibase-I; EC 3.6.1.13) hydrolyzes protein-glycating ADP-ribose. The results show NAPQI-dependent alterations of ADPRibase-I leading to strong inhibition: a fast Km increase produced by low concentrations, and a time-dependent Vmax decrease by higher NAPQI concentrations. Both effects were prevented by thiols, but not reverted by them, nor by gel filtration of NAPQI-treated enzyme. Liver ADPRibase-I can be a target of NAPQI-dependent arylation. The inhibition or inactivation of the enzyme would contribute to increasing the free ADP-ribose concentration and nonenzymatic ADP-ribosylation, which is coherent with results linking free ADP-ribose-producing pathways to acetaminophen toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / analogs & derivatives
  • Acetaminophen / pharmacokinetics*
  • Acetaminophen / toxicity*
  • Animals
  • Benzoquinones / pharmacology*
  • Chromatography, Gel
  • Cytosol / enzymology
  • Dithiothreitol / pharmacology
  • Imines / pharmacology*
  • Kinetics
  • Liver / enzymology*
  • Pyrophosphatases / antagonists & inhibitors
  • Pyrophosphatases / isolation & purification
  • Pyrophosphatases / metabolism*
  • Rats

Substances

  • Benzoquinones
  • Imines
  • Acetaminophen
  • ADP-ribose pyrophosphatase I
  • Pyrophosphatases
  • N-acetyl-4-benzoquinoneimine
  • Dithiothreitol