Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

摘要: Interpretations of elevated blood levels alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, mechanisms driving release have not been explored experimentally. The usefulness ALT and related biomarkers will improve by developing mechanism-based explanations can be expanded elaborated incrementally. We provide means to challenge ability closely model generate patterns simulated hepatic scale (or not) quantitatively similar wet-lab validation targets, which are plasma values following acetaminophen (APAP) exposure in mice. build on a published mechanism helps explain generation characteristic spatiotemporal features APAP hepatotoxicity within lobules. Discrete event agent-oriented software methods most prominent. instantiate leverage small constellation concrete mechanisms. Their details during execution help bring into focus ways particular sources uncertainty become entangled with cause-effect across several levels. amounts virtual mice directly target individual A experiment comprises set Monte Carlo simulations. sufficiency four potentially explanatory theories release. first tested failed achieve initial target, but each three others succeeded. Results one matched all quantitatively. It explains how externalization combined consequence lobular-location-dependent cellular damage hepatocyte death. Falsification more) provides new knowledge incrementally shrinks modularity biomimicry our models enable seamless transition humans.