Paracetamol, 3-monoalkyl- and 3,5-dialkyl derivatives: comparison of their hepatotoxicity in mice.
The effect of 3-monoalkyl and 3,5-dialkyl substitution (R = CH3, C2H5, and i-C3H7) on hepatotoxicity of the analgesic paracetamol was studied in vivo. To that purpose, varying doses of paracetamol and six alkyl-substituted derivatives were orally administered to male DAP mice. Paracetamol caused hepatotoxicity as judged from elevation of plasma transaminase activities and liver histopathology at a dose of 3.95 mmol/kg. All 3-monoalkyl-substituted derivatives of paracetamol caused centrilobular necrosis at oral doses of 4.40, 4.85, and 5.30 mmol/kg of 3-methyl-, 3-ethyl-, and 3-isopropyl derivatives, respectively. Oral dosage of the 3,5-dialkyl-substituted derivatives up to 6.25 mmol/kg did not result in hepatotoxicity. Since 3,5-dialkyl substitution of paracetamol does not reduce the analgesic activity, the observed prevention of paracetamol-induced hepatic necrosis by 3,5-dialkyl substitution may offer perspectives for the design of safer analgesics.
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D009336:Necrosis; D013329:Structure-Activity Relationship
D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase