Modulation of AhR-dependent signaling by PPARb/d

Pennsylvania State University, The, University Park PA

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Abstract

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-[unreadable] (PPAR[unreadable]-also referred to as PPAR[unreadable]) may also alter AhR-dependent signaling by modulating cytochrome P450 (CYP) expression. In the absence of PPAR[unreadable]/[unreadable] 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[unreadable]/[unreadable] could significantly alter this balance. The central hypothesis of this proposal is that the PPAR[unreadable]/[unreadable] modulates the metabolic fate of PAH. We will determine the functional significance of PPAR[unreadable]/[unreadable]-dependent modulation of AhR-mediated signaling by testing the hypothesis that PPAR[unreadable]/[unreadable] 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.