Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments
Cascading events within Lobules (A) During a Mouse Analog experiment that used MGNZ-Mechanism and started with a single toxic APAP dose (maps to approximately 300 mg/kg), measurements were made within the three illustrated 5-grid-space-wide regions: PP region adjacent to lobule entrance; CV region adjacent to CV; and Midzonal region in between. The experiment used 332 Monte Carlo variants of the same Mouse Analog. (B) Amounts in Mouse Body. The function of Extracellular Marker is analogous to that of an internal standard. It behaves the same as APAP, except that it is excluded from Cells and is not eliminated. The APAP profile during the experiment maps quantitatively to blood level profile in mice. G&S are transported out of Hepatocytes and accumulate in Mouse Body. Data in C and G-J are 100-second moving averages from the experiment described in A. (C) NAPQI profiles in each region reflect APAP profiles. APAP Blood levels adjacent to PP spaces are dramatically reduced as it distributes into the large number of accessible Hepatocytes. APAP in Blood in CV region partitions into far fewer Cells, so that per Cell concentration adjacent to CV at early times is actually greater than that in Cells adjacent to lobule entrance. (D-F) Histograms for number of Hepatocyte (Hep) Death events per second. Earliest Hepatocyte Deaths are seen at 1.2 hours after APAP dosing; Death trigger events occur earlier. (G) Amounts of G&S in each region. (H) Cumulative mean GSH Depletion events. (I) Mean amounts of mitoD: more than 5 mitoD per Hepatocyte triggers Death. Significant mitoD accumulation begins only after GSH Depletion. (J) Cumulative mitoD Mitigation events. Total Hepatocytes for 332 Monte Carlo variants: 4,648,000.