RESVERATROL INDUCTION OF GENE EXPRESSION VIA ACTIVATION OF CAR AND NRF2

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Red wine consumption in the United States has increased because the popular media and medical community have touted its antioxidant properties and potential to fight disease such as atherosclerosis and cancer. Thus, understanding the protective properties of resveratrol and determining appropriate rodent models to study them is important for public health. In cells and rat liver, resveratrol treatment increases the expression of several genes regulated by the Antioxidant Response Element (ARE), which are important for Phase-I and -II metabolism. A mechanism by which resveratrol may exert its protective properties is through induction of gene expression via activation AREs. Preliminary data demonstrates that trans-stilbene oxide (TSO), a chemical structurally similar to resveratrol, increases the mRNA expression of some genes encoding Phase-I and -II drug metabolizing enzymes (DMEs), and drug transporters. TSO activates two transcription factors that regulate expression of DMEs and transporters, namely the Constitutive Androstane Receptor (CAR) and Nuclear Factor-E2-Related Factor (NRF2). We hypothesize that resveratrol induces the expression of genes for Phase-I, and -II DMEs, as well as transporters, in hepatocytes through activation of CAR and NRF2. Specific aim 1 will determine whether resveratrol treatment increases Phase-I, -II DME expression and transporter expression in human hepatocytes and mouse liver. Specific aim 2 will determine whether resveratrol activates CAR and Nrf2 using transient transfection and in vivo luciferase assays with Nuclear Receptor-1 and ARE/EpRE-luciferase reporter constructs, as well as transgenic mice possessing an ARE-luciferase reporter. Specific aim 3 will determine whether RES pretreatment affects acetaminophen metabolism, disposition, and toxicity. Together, these studies will determine whether resveratrol exposure alters expression of human and genes for DMEs and transporters, and whether a species similarity in regulation of these genes exists. The studies will also determine whether resveratrol exerts its protective properties through activation of nuclear receptors, specifically CAR and Nrf2.