Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2016 Nov 17;2:16032. doi: 10.1038/npjsba.2016.32

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

Copyright © 2016 The Author(s)

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

PMC Copyright notice

Multi-formalism simulation integrating cortisol signaling with the human Recon2 GSMN reveals a drug interaction with estradiol clearance. (a) The Petri Net diagram of network connectivity created in the Snoopy editor, with overlaid comments for clarity. Color and symbol size has been manually set to match SBGN molecule types and transition types specific to QSSPN. The PN connectivity to implement a timer for administering a network perturbation (cortisol burst), is contained within a coarse transition and shown as an insert. (b) Simulation of glucose and lactate dynamics in the blood physiological compartment, demonstrating a convergence to physiologically realistic steady states. Perturbation of the system through a simulated cortisol infusion starting after 500 min elicits a dynamic alteration in the signaling network, resulting in (c) a predicted increase in CYP34A protein levels, which is confirmed in primary human hepatocytes. The increased expression of CYP3A4 protein is predicted to increase flux through reactions catalyzed by this enzyme, leading to: (d) degradation of excess cortisol and establishment of new steady state; (e) a drug–drug interaction for a second CYP3A4 substrate (estradiol), contained within the GSMN, leading to a decrease in it’s steady-state level. The predicted increase in CYP3A4 activity following cortisol exposure is confirmed in primary human hepatocytes (f), as is the enhanced rate of estradiol clearance (g). FBA, Flux Balance Analysis; GSMN, Genome-Scale Metabolic Network; mRNA, messenger RNA; QSSPN, Quasi-Steady State Petri Net. **P<0.01, ***P<0.001.