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Title: Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses

Abstract

Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2.more » As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a possibly common mechanism for the hormetic responses observed with many mutagens/carcinogens whose activities require bioactivation by phase I enzymes. Feedforward control, often operating in combination with negative feedback regulation in a homeostatic system, may be a general control theme responsible for steady-state hormesis.« less

Authors:
 [1];  [2];  [2]
  1. Division of Translational Biology, Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States)
  2. Division of Computational Biology, Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States)
Publication Date:
OSTI Identifier:
21272583
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 237; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2009.04.005; PII: S0041-008X(09)00150-1; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL ADAPTATION; CARCINOGENS; CONTROL; CONTROL SYSTEMS; CYSTEINE; DETOXIFICATION; DIFFERENTIAL EQUATIONS; GLUTATHIONE; INDUCTION; LIGASES; METABOLISM; RECEPTORS; STEADY-STATE CONDITIONS; TOXICITY; TRANSCRIPTION FACTORS

Citation Formats

Zhang Qiang, Jingbo, Pi, Woods, Courtney G, ExxonMobil Biomedical Sciences, Annandale, NJ 08801, and Andersen, Melvin E. Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses. United States: N. p., 2009. Web. doi:10.1016/j.taap.2009.04.005.
Zhang Qiang, Jingbo, Pi, Woods, Courtney G, ExxonMobil Biomedical Sciences, Annandale, NJ 08801, & Andersen, Melvin E. Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses. United States. https://doi.org/10.1016/j.taap.2009.04.005
Zhang Qiang, Jingbo, Pi, Woods, Courtney G, ExxonMobil Biomedical Sciences, Annandale, NJ 08801, and Andersen, Melvin E. 2009. "Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses". United States. https://doi.org/10.1016/j.taap.2009.04.005.
@article{osti_21272583,
title = {Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses},
author = {Zhang Qiang and Jingbo, Pi and Woods, Courtney G and ExxonMobil Biomedical Sciences, Annandale, NJ 08801 and Andersen, Melvin E},
abstractNote = {Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a possibly common mechanism for the hormetic responses observed with many mutagens/carcinogens whose activities require bioactivation by phase I enzymes. Feedforward control, often operating in combination with negative feedback regulation in a homeostatic system, may be a general control theme responsible for steady-state hormesis.},
doi = {10.1016/j.taap.2009.04.005},
url = {https://www.osti.gov/biblio/21272583}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 237,
place = {United States},
year = {Mon Jun 15 00:00:00 EDT 2009},
month = {Mon Jun 15 00:00:00 EDT 2009}
}