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Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital
Citation:
El-Masri, H., S. Hester, C. Wood, I. Shah, D. Wolf, AND C. Corton. Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital. Presented at Society of Toxicology, March 10 - 14, 2013.
Impact/Purpose:
This abstract will be presented at the Society of Toxicology meeting, March 10-14, 2013, San Antonio, TX.
Description:
Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast database, and in vivo outcomes in the US EPA ToxRef database to link CAR activation to a proposed adverse outcome pathway (AOP) of hepatic tumors. Key in vivo pathological events for this proposed hepatic tumor AOP are similar to those of other non-genotoxic receptor-mediated chemicals (i.e., hypertrophy, cellular proliferation, preneoplastic foci, and neoplasia), highlighting the importance of upstream biological mechanisms mediating the early proliferative signals of CAR activation. Using phenobarbital (PB), a known rodent tumor promoter and CAR activator, we developed a computational model for the early initiating events of CAR activation leading to its nuclear translocation. Based on literature evidence, the computational model describes the cascade of biological events leading to CAR nuclear translocation. These events are initiated by PB activation of Adenylyl Cyclase (AC) leading to an increase in the rate of ATP transformation to cyclic AMP. In turn, cyclic AMP increases intercellular calcium levels which inhibit the activity of AC via a negative feedback loop mechanism. However, the resulting transient increase in cyclic AMP levels activates protein phosphatase 2A (PP2A) which inhibits ERK. This inhibition is required for the nuclear translocation of CAR and the subsequent binding to a PB-enhancer module (PBREM) indicated by CYP2B6 gene induction. Future work will bridge these events with key targets mediating proliferative responses in the proposed AOP for hepatic nuclear receptor mediated carcinogenesis. Our computational systems model illustrates the impact of early events for dose-response modeling of receptor-mediated AOPs. This abstract does not reflect EPA policy.