Effects of Xenobiotics on CYP26 Activity and Retinoic Acid Homeostasis

描述(申请人提供)：这项建议的长期目标是确定外源物质和CYP26酶之间的相互作用，这些相互作用会导致血浆和不同组织中全反式维甲酸(RA)浓度的变化。这一点很重要，因为准确控制RA浓度对生殖、胎儿和胎盘发育、上皮细胞的维持、免疫和细胞凋亡的调节以及癌症的预防和治疗至关重要。通过抑制或诱导负责RA代谢的酶来改变RA消除的化合物有可能对个人健康造成多种有害影响。这项拨款提案的中心假设是，CYP26酶调节循环中RA的浓度，并控制体内RA的清除。这一假说将通过三个特定的目标来检验，这些目标旨在提供一个全面的表征CYP26A1和CYP26B1在调节RA动态平衡中的作用。这项建议的第一个具体目的是证明CYP26A1和CYP26B1是成人组织中主要的RA羟基酶。第二个特异性目的是鉴定细胞色素P26A1和细胞色素P26B1的异源和内源性配体。目的研究外源化合物对人体组织和细胞系细胞色素P26A1和细胞色素P26B1表达及维甲酸代谢的影响。这些目标的结果将为了解CYP26A1和CYP26B1的功能和底物特异性提供重要的基础知识，这两种酶是研究较少且特性较差的两种P450酶。细胞维甲酸浓度的严密调节对于正常生殖、免疫功能、维持健康的上皮细胞和骨骼健康以及对细胞凋亡和细胞分裂的调节是必不可少的。因此，控制细胞维甲酸代谢的过程的改变可能会对个人健康造成多种有害影响。这项建议旨在表征外源物质和维甲酸之间的相互作用，代谢细胞色素P26酶会改变维甲酸的代谢和清除，并可能导致不良反应。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to identify interactions between xenobiotics and CYP26 enzymes that lead to altered all-trans retinoic acid (RA) concentrations in plasma and in different tissues. This is important because accurate control of RA concentrations is critical for reproduction, fetal and placental development, maintenance of epithelia, regulation of immunity and apoptosis and cancer prevention and treatment. Compounds that alter RA elimination by inhibiting or inducing the enzymes responsible for RA metabolism have the potential to cause multiple detrimental effects on individuals' health. The central hypothesis of this grant proposal is that CYP26 enzymes regulate circulating RA concentrations and control the clearance of RA in vivo. This hypothesis will be tested by the three specific aims designed to provide a comprehensive characterization of the role of CYP26A1 and CYP26B1 in regulating RA homeostasis. The first specific aim of this proposal is to demonstrate that CYP26A1 and CYP26B1 are the major RA hydroxylases in adult human tissues. The second specific aim is to identify xenobiotic and endogenous ligands of CYP26A1 and CYP26B1. Aim 3 will test the effect of selected xenobiotics on CYP26A1 and CYP26B1 expression and RA metabolism in human tissues and cell lines. The results of these aims will provide important basic understanding of the function and substrate specificity of CYP26A1 and CYP26B1, two understudied and poorly characterized P450 enzymes. Tight regulation of cellular retinoic acid concentrations is essential for normal reproduction, immune competence, maintenance of healthy epithelia and bone health and for regulation of apoptosis and cell division. As such, alteration of the processes that control cellular retinoic acid metabolism can cause multiple detrimental effects on an individual's health. This proposal aims at characterizing interactions between xenobiotics and retinoic acid metabolizing CYP26 enzymes that alter retinoic acid metabolism and clearance and can lead to adverse effects.