Rat liver ADP-ribose pyrophosphatase-I as an in vitro target of the acetaminophen metabolite N-acetyl-p-benzoquinoneimine.
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.
Ribeiro
J M
JM
Unidad de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Extremadura, Badajoz, Spain.
Agudo
A
A
Costas
M J
MJ
Cameselle
J C
JC
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D002850:Chromatography, Gel; D003600:Cytosol / Q000201:enzymology; D004229:Dithiothreitol / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats
D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C058796:ADP-ribose pyrophosphatase I; D011755:Pyrophosphatases; C028473:N-acetyl-4-benzoquinoneimine; D004229:Dithiothreitol