Simulating plausible mechanisms for changing hepatic xenobiotic clearance patterns

Abstract

No concrete, causal, mechanistic theory is available to explain how different hepatic zonation patterns of P450 isozyme levels and hepatotoxicity emerge following dosing with different compounds. We used the synthetic method of modeling and simulation to discover, explore, and experimentally challenge a concrete mechanism that shows how and why biomimetic zonation patterns emerge and change within agent-based analogues. We hypothesized that those mechanisms have counterparts in rats. Mobile objects map to compounds. One analogue is comprised of a linear sequence of 20 identical, quasi-autonomous functional units called sinusoidal segments (SSs). SSs detect and respond to compound-generated response signals and the local level of a gradient. Each SS adapts to new information with the objective of improving efficiency (lowering costs). Upon compound exposure, analogues developed a variety of patterns that were strikingly similar to those reported in the literature.