Modulation of AhR-dependent signaling by PPARb/d

芳香烃受体(AhR)介导I相和II相异源代谢酶在暴露于化学致癌物包括多环芳烃(PAH)时的表达增加。我们发现，过氧化物酶体增殖物激活受体β(PPARβ-又称PPARδ)也可能通过调节细胞色素P450(CyP)的表达来改变AHR依赖的信号转导。在没有多环芳烃受体β/δ表达的情况下，施加多环芳烃后，细胞色素P450 1B1和细胞色素P450 1 A1以及某些II相酶的表达不会增加。由于致癌物的生物激活(I期)和解毒(II期)之间存在平衡，这是由AHR依赖的途径介导的，这表明PPARβ/δ可以显著改变这种平衡。这一建议的中心假设是，多环芳烃受体β/δ调控多环芳烃的代谢命运。我们将通过检测多环芳烃在小鼠皮肤、原代角质形成细胞中的代谢命运以及氧化β/δ损伤来验证多环芳烃依赖的生物激活和多环芳烃的解毒之间的平衡这一假设，并在人的角质形成细胞中验证这些变化，从而确定多环芳烃受体依赖的β/δ调控AhR介导的信号转导的功能意义。

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.