Effects of Xenobiotics on CYP26 Activity and Retinoic Acid Homeostasis

描述（由申请人提供）：本申报的长期目标是确定外源药物和CYP26酶之间的相互作用，从而改变血浆和不同组织中全反式维甲酸（RA）浓度。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、上皮细胞维持、免疫和细胞凋亡调节以及癌症预防和治疗至关重要。通过抑制或诱导负责类风湿性关节炎代谢的酶来改变类风湿性关节炎消除的化合物有可能对个体健康造成多重有害影响。本研究的中心假设是CYP26酶调节循环中的RA浓度并控制体内RA的清除。这一假设将通过三个具体目标来验证，这些目标旨在全面表征CYP26A1和CYP26B1在调节RA稳态中的作用。本提案的第一个具体目的是证明CYP26A1和CYP26B1是成人组织中主要的RA羟化酶。第二个具体目标是鉴定CYP26A1和CYP26B1的外源性和内源性配体。Aim 3将测试选定的外源药物对人体组织和细胞系中CYP26A1和CYP26B1表达和RA代谢的影响。这些目标的结果将为CYP26A1和CYP26B1的功能和底物特异性提供重要的基本认识，这两种P450酶的研究尚不充分，表征也不充分。细胞维甲酸浓度的严格调节对于正常生殖、免疫能力、维持健康的上皮和骨骼健康以及调节细胞凋亡和细胞分裂是必不可少的。因此，控制细胞维甲酸代谢过程的改变会对个人健康造成多重有害影响。本研究旨在描述外源药物与维甲酸代谢CYP26酶之间的相互作用，从而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.