Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide.
1. The effects of racemic thalidomide (D[+]/L[-] alpha-phthalimido-glutarimide) on acetaminophen (AAP)-induced hepatitis were tested in male NMRI mice (n = 133) and quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). 2. A 2.1-fold increase of GOT and a 1.9-fold increase of GPT activities (P < 0.001) were observed in mice treated perorally with 500 mg/kg of AAP plus 150 mg/kg of thalidomide (Thal). In the absence of AAP, Thal did not display any detectable hepatotoxic effects. 3. The Thal-induced exacerbation of AAP hepatotoxicity was completely inhibited by nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP) (P < 0.0001), suggesting a possible influence of Thal on the hepatic metabolism of NAD-adenoribosylation. 4. We see the main application of nicotinic acid amide as for the combinational use in pharmaceutical preparations of AAP in order to avoid hepatic damage in patients treated with AAP and Thal.
Kröger
H
H
Deutsches RheumaForschungsZentrum (German Rheumatology Research Center), Department of Biochemistry, Berlin, Germany.
Klewer
M
M
Grätz
R
R
Dietrich
A
A
Ockenfels
H
H
Miesel
R
R
D000082:Acetaminophen / Q000009:adverse effects*; D000410:Alanine Transaminase / Q000187:drug effects; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects; D004347:Drug Interactions; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009536:Niacinamide / Q000494:pharmacology*; D013792:Thalidomide / Q000494:pharmacology*
D009536:Niacinamide; D000082:Acetaminophen; D013792:Thalidomide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase