The influence of antagonists of poly(ADP-ribose) metabolism on acetaminophen hepatotoxicity.
An array of therapeutically used analgetic and antirheumatic drugs causes severe liver damage. The present study investigates the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation reactions in analgesics-induced hepatic injury. Male NMRI mice were treated perorally with 500 mg/kg of acetaminophen, and the activities of both glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) were determined in serum. In addition, the activity of poly(ADP-ribose)polymerase (PARP) was quantified in liver cell nuclei. While the PARP-activity remained essentially unchanged, the acetaminophen-induced release of both GOT and GPT from injured liver cells could be inhibited by 90-99%, when mice were injected additionally with the selective PARP-inhibitors nicotinic acid amide, benzamide, caffeine, theophyline, and thymidine, respectively. We see the main application of inhibitors of adenoribosylation reactions as for the combinational use in pharmaceutical preparations of analgesics and antirheumatic drugs in order to avoid hepatic damage.
Kröger
H
H
Department of Biochemistry, German Rheumatology Research Center, Berlin.
Ehrlich
W
W
Klewer
M
M
Grätz
R
R
Dietrich
A
A
Miesel
R
R
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D011065:Poly(ADP-ribose) Polymerases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase