Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments
(A) Experiments capable of challenging the NAPQI zonation hypothesis must demonstrate four characteristics. 1) Components are concrete and biomimetic. 2) Mechanism events during execution are observable and independent of phenomena being generated. 3) Qualitative and quantitative similarity (or lack thereof) can be established between target and Mouse Analog phenomena. 4) Means exist to incrementally strengthen claims that details of causal cascades in mice are strongly analogous —quantitatively similar—to details of Mouse Analog’s causal cascade within and across multiple levels. (B) Virtual experiments designed to challenge the NAPQI zonation hypothesis focus on Metabolism Phase events and key early events within the Toxicity Phase of injury . Although illustrated as a sequential cascade, each event executes independently in pseudo-random order each time step. All events are stochastic. Some event probabilities are Lobule location-dependent. An APAP object maps to a small fraction of an actual APAP dose, which for this work maps to 300 mg/kg. G&S objects represent APAP-glucuronide and APAP-sulfate plus all other inactive metabolites. A glutathione (GSH) Depletion event maps to depletion of a portion of a hepatocyte’s basal GSH. Mitochondrial Damage objects (mitoD) map to conflation of all influential damage products occurring within mitochondria . Each mitoD may undergo one amplification event resulting in ≤ 6 additional mitoD; doing so enables downstream events to be finer grain than Metabolism Phase events. A mitoD Mitigation event maps to processes that advance recovery; it maps to an incremental reduction in mitochondrial disruption and damage.