Toxicity Monitoring with Primary Cultured Hepatocytes Underestimates the Acetaminophen-Induced Inflammatory Responses of the Mouse Liver





<i>In vitro</i> gene expression profiling with isolated hepatocytes has been used to assess the hepatotoxicity of certain chemicals because of animal welfare issues. However, whether an <i>in vitro</i> system can completely replace the <i>in vivo</i> system has yet to be elucidated in detail. Using a focused microarray established in our laboratory, we examined gene expression profiles in the mouse liver and primary cultured hepatocytes after treatment with different doses of acetaminophen, a widely used analgesic that frequently causes liver injury. The acute hepatotoxicity of acetaminophen was confirmed by showing the induction of an oxidative stress marker, heme oxygenase-1, elevated levels of serum transaminase, and histopathological findings. <i>In vivo</i> microarray and network analysis showed that acetaminophen treatment provoked alterations in relation to the inflammatory response, and that tumor necrosis factor-α plays a central role in related pathway alterations. By contrast, pathway analyses in <i>in vitro</i> isolated hepatocytes did not find such prominent changes in the inflammation-related networks compared with the <i>in vivo</i> situation. Thus, although <i>in vitro</i> gene expression profiles are useful for evaluating the direct toxicity of chemicals, indirect toxicities including inflammatory responses mediated by cell-cell interactions or secondary toxicity due to pathophysiological changes in the whole body may be overlooked. Our results indicate that the <i>in vitro</i> hepatotoxicity prediction system using isolated hepatocytes does not fully reflect the <i>in vivo</i> cellular response. An <i>in vitro</i> system may be appropriate, therefore, for high throughput screening to detect the direct hepatotoxicity of a test compound.


  • Tohoku journal of experimental medicine

    Tohoku journal of experimental medicine 225(4), 263-272, 2011-12-01

    Tohoku University Medical Press

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