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Unraveling the effect of intra- and intercellular processes on acetaminophen-induced liver injury

Heldring, M. M., Shaw, A. H., Beltman, J. B.·2022·npj Systems Biology and Applications
DOI 10.1038/s41540-022-00238-5PMC PMC9357019
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Abstract

In high dosages, acetaminophen (APAP) can cause severe liver damage, but susceptibility to liver failure varies across individuals and is influenced by factors such as health status. Because APAP-induced liver injury and recovery is regulated by an intricate system of intra- and extracellular molecular signaling, we here aim to quantify the importance of specific modules in determining the outcome after an APAP insult and of potential targets for therapies that mitigate adversity. For this purpose, we integrated hepatocellular acetaminophen metabolism, DNA damage response induction and cell fate into a multiscale mechanistic liver lobule model which involves various cell types, such as hepatocytes, residential Kupffer cells and macrophages. Our model simulations show that zonal differences in metabolism and detoxification efficiency are essential determinants of necrotic damage. Moreover, the extent of senescence, which is regulated by intracellular processes and triggered by extracellular signaling, influences the potential to recover. In silico therapies at early and late time points after APAP insult indicated that prevention of necrotic damage is most beneficial for recovery, whereas interference with regulation of senescence promotes regeneration in a less pronounced way.

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  • These patterns of toxicity are in agreement with the increased expression of the perivenous markers CYP2E1 and CYP3A4 in the liver MPS, which drive APAP hepatotoxicity, and recapitulate in vivo APAP toxicity profiles.

    “Notably, these patterns of toxicity are in agreement with the increased expression of the perivenous markers CYP2E1 and CYP3A4 in the liver MPS, which drive APAP hepatotoxicity, and recapitulate in vivo APAP toxicity profiles [37] .”

    From 3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation (2023) · cites this paper as [37]

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Cited by

Sorted by citations

Authors
Heldring, M. M., Shaw, A. H., & Beltman, J. B.
ORCID
Venue
npj Systems Biology and Applications
Publisher
Springer Science and Business Media LLC
Published
2022-08-06
Volume
8
Issue
1
ISSN
2056-7189
DOI
10.1038/s41540-022-00238-5
PMC
PMC9357019
Cited by
23
References
10
Language
en
Licence
Funders
Innovative Medicines Initiative (777365)

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