title: Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.
abstract: Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.forename: C David
authors.initials: CD
authors.lastname: Williams
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Xie
authors.forename: Anup
authors.initials: A
authors.lastname: Ramachandran
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000235:genetics / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D058633:Antipyretics / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D024101:Mitochondrial Proteins; D000082:Acetaminophen; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase; D048670:MAP Kinase Kinase 4