Deferoxamine delays the development of the hepatotoxicity of acetaminophenin mice

The hepatotoxicity of acetaminophen is conventionally ascribed to metabolis m by CYP450 to N-acetyl-p-benzoquinone imine and covalent binding to protei ns. We investigated a potential role for oxidative stress by determining th e effect of the ferric chelator deferoxamine (Desferal) on acetaminophen (p aracetamol)-induced hepatotoxicity in mice. Administration of deferoxamine (75 mg/kg) 1 h after a toxic dose of acetaminophen (300 mg/kg) significantl y delayed the development of the toxicity without altering covalent binding . In saline-treated mice serum ALT was 18 +/- 2 IU/l. In acetaminophen-trea ted mice serum alanine aminotransferase (ALT) was 779 +/- 271 at 2 h, 7421 +/- 552 IU/l at 4 h, 5732 +/- 523 IU/l at 8 h, and 5984 +/- 497 IU/l at 24 h. In acetaminophen plus deferoxamine-treated mice, serum ALT was 80 +/- 10 at 2 h, 472 +/- 74 IU/l at 4 h, 2149 +/- 597 IU/l at 8 h, and 5766 + 388 a t 24 h. Deferoxamine at 1 h after acetaminophen did not decrease serum ALT at 12 h; however, deferoxamine at 1 and 4 h, or deferoxamine at 1 h plus N- acetylcysteine at 4 h to replete hepatic glutathione, decreased the toxicit y from 5625 +/- 310 IU/l to 3436 +/- 546 IU/l and 3003 +/- 282 IU/l, respec tively. Deferoxamine plus N-acetylcysteine at 1.25 h after acetaminophen wa s more effective at decreasing the 24 h toxicity than N-acetylcysteine alon e. In acetaminophen treated mice, higher doses of deferoxamine (150-300 mg/ kg) at 1 h greatly increased the observed hepatotoxicity at 4 h in a dose r esponsive manner, but deferoxamine alone was nontoxic. (C) 1999 Elsevier Sc ience Ireland Ltd. All rights reserved.