Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms
Fig 2
Events that can occur within each vHPC.
Arrows indicate discrete probabilistic events (not continuous processes) that may occur during a particular simulation cycle. (A) These features and events are parameterized the same as in Smith et al. [8]. There is a direct mapping between the probability of an APAP Metabolism event and average metabolic capacity of hepatocytes at various PP-to-PC locations. Red arrow: event probability or value decreases PP-to-PC. Green arrow: event probability increases PP-to-PC. A NAPQI removal event depletes Glutathione (GSH). Once GSH falls below the vHPC’s GSH Depletion Threshold, each subsequent NAPQI removal event is paired with creation of one of two types of Damage Product, either a MitoD object (maps to mitochondrial damage products) or a nonMitoD object (maps to non-mitochondrial damage products). Amounts of MitoD and nonMitoD are amplified [8]. A MitoD or nonMitoD object may be removed, which maps to a damage mitigation process. The probability of a MitoD removal event decreases PP-to-PC, whereas the probability of a nonMitoD removal event increases PP-PC [8]. (B) The virtual counterparts of two types of damage-induced ALT externalization events are illustrated. 1) Accumulation of MitoD objects above an ALT Leakage Threshold triggers ALT leakage and subsequent ALT externalization. 2) Accumulation of nonMitoD objects above an ALT Leakage Threshold triggers ALT leakage and subsequent ALT externalization. Both ALT Leakage Threshold values are the same. 3) Both of the preceding processes may operate concurrently. The contributions 1–3 to explanations of the target data were investigated separately. Externalized ALT accumulates in Mouse Body. (C) Independent of the events in B, accumulation of MitoD above a Necrosis threshold triggers Necrosis, the same as in Smith et al. [8]. Once Necrosis is triggered, there is a delay—a Monte Carlo sampled lag time—before the vHPC becomes Necrotic (maps to cell death) and all remaining ALT is externalized. The minimum ALT Leakage lag time is less than the minimum lag time for Necrosis Triggered → Necrotic. Parameterizations within B and C are independent of a vHPC’s PP-to-PC location. Nevertheless, ALT Externalization within B and C is dependent on a vHPC’s PP-to-PC location because of the location-dependent events in A (red and green arrows). Externalized ALT exits a SS, enters the CV, and is transferred to Mouse Body the same as unmetabolized APAP. ALT in Mouse Body maps quantitatively to plasma ALT values.