Modulation of AhR-dependent signaling by PPARb/d

Project: Research project

Description

The aryl hydrocarbon receptor (AhR) mediates increased expression of phase I and II xenobiotic metabolizing enzymes in response to exposure to chemical carcinogens including polycyclic aromatic hydrocarbons (PAH). We have discovered that peroxisome proliferator-activated receptor- (PPAR -also referred to as PPAR ) may also alter AhR-dependent signaling by modulating cytochrome P450 (CYP) expression. In the absence of PPAR / expression, increased expression of CYP1B1 and CYP1A1 and some phase II enzymes does not occur after application of PAHs. Since there is a balance between bio-activation (phase I) and detoxification (phase II) of carcinogens that is mediated by AhR-dependent pathways, this suggests that PPAR / could significantly alter this balance. The central hypothesis of this proposal is that the PPAR / modulates the metabolic fate of PAH. We will determine the functional significance of PPAR / -dependent modulation of AhR-mediated signaling by testing the hypothesis that PPAR / modulates the balance between AhRdependent bio-activation and detoxification of PAH by examining the metabolic fate of PAH as well as oxidative DNA damage in mouse skin, primary keratinocytes;and verifying these changes in human keratinocytes.
StatusFinished
Effective start/end date7/17/096/30/11

Funding

  • National Institutes of Health: $286,572.00
  • National Institutes of Health: $307,021.00

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Aryl Hydrocarbon Receptors
Peroxisome Proliferator-Activated Receptors
Polycyclic Aromatic Hydrocarbons
Keratinocytes
Phase I Metabolic Detoxication
Carcinogens
Cytochrome P-450 CYP1A1
Xenobiotics
Enzymes
Cytochrome P-450 Enzyme System
DNA Damage
Skin