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Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments

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Mouse Analog components and their organization (A) Mouse Analog comprises a Liver, Mouse Body, as well as a space to contain dose; the space enables simulating intravenous, intraperitoneal, and intragastric dosing. During execution, each discrete time step maps to 1 second. (B) A Liver comprises Monte Carlo-determined Lobule variants. (C) A Lobule comprises a directed graph with a concrete Sinusoid Segment (SS) object (a software agent) at each graph node. The Lobular configurations used herein were validated earlier; they are the result of cycling many times through the Iterative Refinement Protocol (described later) and successfully achieving several quantitative Target Attributes having stringent Similarity Criteria [912]. All flow paths follow the directed graph. Bile (dotted green) flows separately from blood (solid red) but is not a factor for the hypotheses tested herein. Periportal (PP) to CV gradients provided intra-Lobular location information to each Hepatocyte. (D) Each Sinusoid Segment configures a parsimony-guided multilevel variety of components so that during execution it functions as an analog of sinusoid components and features averaged across many lobules; Sinusoid Segment dimensions are Monte Carlo determined to mimic hepatic variability. Cell objects occupy most of Endothelial Cell (99%) and Hepatocyte (90%) spaces. APAP objects enter and exit a Sinusoid Segment via Core and Interface, percolate stochastically through accessible spaces influenced by configuration-controlled local flow, and, if not metabolized, exit to CV and return to Mouse Body. (E) Cells in Endothelial space control APAP entry and exit and contain a probability-specified number of Binders; for this work, we only required that they bind and release APAP. Hepatocytes use three previously validated event management modules [13], which control 1) material entry and removal, 2) binding and object transformations, and 3) up- and down-regulation of events such as Metabolism (not used for this work).

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doi: https://doi.org/10.1371/journal.pcbi.1005253.g002