Effects of Xenobiotics on CYP26 Activity and Retinoic Acid Homeostasis

描述（由申请方提供）：本提案的长期目标是确定外源性物质与CYP 26酶之间的相互作用，这些相互作用导致血浆和不同组织中全反式维甲酸（RA）浓度改变。这一点很重要，因为准确控制RA浓度对于生殖、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消除的化合物具有对个体健康造成多种有害影响的潜力。这项拨款提案的中心假设是，CYP26酶调节循环RA浓度和控制体内RA的清除。这一假设将通过三个特定目的进行检验，旨在全面表征CYP26 A1和CYP26 B1在调节RA稳态中的作用。本提案的第一个具体目的是证明CYP26 A1和CYP26 B1是成人组织中主要的RA羟化酶。第二个具体目标是鉴定CYP26 A1和CYP26 B1的异源性和内源性配体。目的3：检测外源性化合物对人组织和细胞系中CYP26A1和CYP26B1表达及RA代谢的影响。这些目标的结果将提供重要的基本了解的功能和底物特异性的CYP26 A1和CYP26 B1，两个研究不足，并不充分的特点P450酶。细胞视黄酸浓度的严格调节对于正常生殖、免疫能力、维持健康上皮细胞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，控制细胞视黄酸代谢的过程的改变可以对个体的健康造成多种有害影响。该提案旨在表征异生物质与改变视黄酸代谢和清除并可能导致不良反应的视黄酸代谢CYP 26酶之间的相互作用。

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.