Computational experiments reveal plausible mechanisms for changing patterns of hepatic zonation of xenobiotic clearance and hepatotoxicity.
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 concrete mechanisms that show how and why biomimetic zonation patterns can emerge and change within agent-based analogues, expecting that those mechanisms may have counterparts in rats. Mobile objects map to compounds. One analogue represents a cross-section through a lobule. It is comprised of 460 identical, quasi-autonomous functional units called sinusoidal segments (SSs). SSs detect and respond to compound-generated response signals and the local level of an endogenous gradient. Each SS adapts by using those signals to adjust (or not) the probability that it will clear a detected compound during the next simulation cycle. The adjustment decision is based on the value of a biomimetic algorithm that is based on an assumed, evolution imposed, genetic mandate that normal hepatocytes resist increasing the cost of their actions. The algorithm estimates the long-term, discounted cost to a given SS of continuing to use its current clearance effort. Upon compound exposure, lobular analogues developed a variety of clearance and hepatotoxicity patterns that were strikingly similar to those reported in the literature. A degree of quantitative validation was achieved against data on hepatic zonation of CYP1A2 mRNA expression caused by three different doses of TCDD (2,3,7,8-tetracholorodibenzo-p-dioxone).
Sheikh-Bahaei
Shahab
S
UCSF/UCB Joint Graduate Group in Bioengineering, University of California, Berkeley, CA 94720, USA.
Maher
Jacquelyn J
JJ
Anthony Hunt
C
C
D000818:Animals; D003198:Computer Simulation; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results; D014118:Toxins, Biological / Q000633:toxicity*; D015262:Xenobiotics / Q000378:metabolism*
D014118:Toxins, Biological; D015262:Xenobiotics; D019388:Cytochrome P-450 CYP1A2