Modulation of AhR-dependent signaling by PPARb/d

芳烃受体（AhR）介导I相和II相异生物质代谢酶的表达增加，以响应暴露于化学致癌物，包括多环芳烃（PAH）。我们已经发现过氧化物酶体增殖物激活受体β（peroxisome proliferator-activated receptor-β，PPARβ-也称为PPARδ）也可以通过调节细胞色素P450（CYP 450）的表达来改变AhR依赖的信号传导。在不存在PPARβ/δ表达的情况下，施用多环芳烃后，CYP 1B 1和CYP 1A 1以及一些II相酶的表达不会增加。由于存在由AhR依赖性途径介导的致癌物的生物活化（阶段I）和解毒（阶段II）之间的平衡，这表明PPARβ/δ可以显著改变这种平衡。该提议的中心假设是，PPARβ/δ调节PAH的代谢命运。我们将通过检测小鼠皮肤、原代角质形成细胞中PAH的代谢命运以及氧化性DNA损伤来检验PPAR β/δ调节AhR依赖性生物活化和PAH解毒之间平衡的假设，并验证人类角质形成细胞中的这些变化，从而确定PPARβ/δ依赖性调节AhR介导的信号传导的功能意义。

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