research project details
Project Title: Endogenous CYP1B1 substrates as AhR ligands
Investigator(s): Gary Perdew
Sponsor: NIH (University of New Mexico)
Environmental Problem Addressed:
Human health risks associated with exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin).
Research Project Objectives:
Specific aims for this project are:
- Determine the mechanism by which the cytochrome P450 1B1 (CYP1B1) regulates AhR (aryl hydrocarbon receptor) transcriptional activity, and
- Identify endogenous AhR ligands/regulators in CV-1 cells and characterize their mechanism of action.
Summary:
The AhR has been shown to be largely responsible for the toxic and tumor-promotional properties of TCDD, especially in rodents. While the human population is exposed to low levels of TCDD and related compounds, the actual long-term health effect(s) from this exposure remain to be elucidated. In order to understand the significance of excessive AhR activation it is essential to understand its normal role in cellular function. In addition, the toxicological significance of prolonged activation of CYP1A1, CYP1B1, and CYP1A2 expression may also be an important aspect of the overall toxic response to TCDD.
Endogenous substrates have been identified for several CYP isoforms, but it remains unknown whether endogenous substrates exist for most if not all CYPs. Many of these substrates may play regulatory roles in directing cell growth, differentiation, and proliferation or in maintaining normal cellular homeostasis.
This project will test the hypothesis that there are significant levels of endogenous ligand(s) for the AhR in CV-1 cells that are metabolized by CYP1B1 and possibly other CYP isozymes, and that CYP-mediated metabolism alters (increases or decreases) the affinity of endogenous ligands for the AhR. This research will establish experimental systems for detecting endogenous AhR ligands and CYP substrates, and lead to identification of these compounds in CV-1 cells, as well as other cell lines.
Results from these studies will provide an improved mechanistic understanding of human health risks associated with exposure to TCDD and other PAHs (polycyclic aromatic hydrocarbons), and enhanced understanding of the role of CYPs in human disease processes and maintenance of normal human health.