Drug-induced liver injury is an important clinical problem and a challenge for drug development.Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the ...Drug-induced liver injury is an important clinical problem and a challenge for drug development.Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models,enormous insight has been gained in the area of predictable hepatotoxins,in particular acetaminopheninduced liver injury,from a broad range of experimental models.Importantly,mechanisms of toxicity obtained with certain experimental systems,such as in vivo mouse models,primary mouse hepatocytes,and metabolically competent cell lines,are being confirmed in translational studies in patients and in primary human hepatocytes.Despite this progress,suboptimal models are still being used and experimental data can be confusing,leading to controversial conclusions.Therefore,this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an example.We compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity,discuss controversial topics in the mechanisms,and assess how these experimental findings can be translated to the clinic.The success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.展开更多
基金Work in the authors' laboratory was supported in part by grants from the National Institutes of Health(R01 DK070195 and R01 AA12916)the National Center for Research Resources(5P20RR021940-07)the National Institute of General Medical Sciences (8 P20 GM103549-07) of the National Institutes of Health.Additional support came from the "Training Program in Environmental Toxicology" T32ES007079-26A2 (to M.R.M.) from the National Institute of Environmental Health Sciences
文摘Drug-induced liver injury is an important clinical problem and a challenge for drug development.Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models,enormous insight has been gained in the area of predictable hepatotoxins,in particular acetaminopheninduced liver injury,from a broad range of experimental models.Importantly,mechanisms of toxicity obtained with certain experimental systems,such as in vivo mouse models,primary mouse hepatocytes,and metabolically competent cell lines,are being confirmed in translational studies in patients and in primary human hepatocytes.Despite this progress,suboptimal models are still being used and experimental data can be confusing,leading to controversial conclusions.Therefore,this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an example.We compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity,discuss controversial topics in the mechanisms,and assess how these experimental findings can be translated to the clinic.The success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.
