The metabolomics of acetaminophen toxicity observed in human biofluids and cultured primary human hepatocytes

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  • March 22, 2019
Creator
  • Winnike, Jason H.
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
Abstract
  • The mechanisms of acetaminophen toxicity are well-established. However, the use of metabolomics to identify small molecule ( 10 kD) inactivation in primary human hepatocyte cultures is original. By tracking the metabolism of 13C tracers, a metabolomic surrogate of enzyme inactivation due to acetaminophen toxicity was discovered. The enzyme inactivation is likely via arylation by the cytochrome P450 bio-activated acetaminophen metabolic product N-acetyl-para-quinonimine. Furthermore, it was observed that the human hepatocytes appeared to be in a stressed metabolic state, due to the lack of glycolysis or glutaminolysis, even in the presence of high insulin and glucose concentrations. This metabolism was compared to that of primary rat hepatocyte cultures, which did not exhibit these features, likely due to absence of stress inducing hormones prior to hepatocyte isolation. This has yet to be described in the literature, likely because this is the first report of the use of 13C-labeled nutrients in primary human hepatocyte cultures.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biomedical Engineering."
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  • Macdonald, Jeffrey
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  • Chapel Hill, NC
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  • Open access
Date uploaded
  • March 18, 2013

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