 Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual ExperimentsAndrew K Smith, Brenden K Petersen, Glen E P Ropella, Ryan C Kennedy, Neil Kaplowitz, Murad Ookhtens and C Anthony Hunt PLOS Computational Biology, 2016, vol. 12, issue 12, 1-24 Abstract: Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule’s central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1) influential variables cannot be controlled, and 2) it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1) a glutathione depletion threshold diminishes in the CV direction; and 2) ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose.Author Summary: Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. Challenging an explanatory mechanism in mice is problematic because variables determining causes and effects cannot be controlled adequately. We circumvent that impediment by performing virtual experiments that challenge the prevailing scientific explanation for the characteristic spatiotemporal pattern of early acetaminophen-induced hepatic necrosis. Virtual mice utilize a biomimetic software liver. Results of virtual experiments provide compelling evidence that the prevailing explanation is insufficient. Without further studies in mice, we discovered a new, marginally more complex explanatory mechanism that met stringent tests of sufficiency. We argue that this virtual causal mechanism and the actual mechanism in mice are strongly analogous within and across multiple biological levels. Variants of the virtual mechanism provide possible explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose. Date: 2016 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1005253 DOI: 10.1371/journal.pcbi.1005253 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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