Effects of Xenobiotics on CYP26 Activity and Retinoic Acid Homeostasis

描述（由申请人提供）：该提案的长期目标是确定异生素和 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的全反式视黄酸 (RA) 浓度发生变化。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。该资助提案的中心假设是 CYP26 酶调节循环 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进行检验，这些目标旨在全面描述 CYP26A1 和 CYP26B1 在调节 RA 稳态中的作用。该提案的第一个具体目标是证明 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 的外源配体和内源配体。目标 3 将测试选定的异生素对人体组织和细胞系中 CYP26A1 和 CYP26B1 表达以及 RA 代谢的影响。这些目标的结果将为 CYP26A1 和 CYP26B1 这两种尚未充分研究且特征不明的 P450 酶的功能和底物特异性提供重要的基本了解。严格调节细胞视黄酸浓度对于正常繁殖、免疫能力、维持健康上皮和骨骼健康以及调节细胞凋亡和细胞分裂至关重要。因此，控制细胞视黄酸代谢过程的改变可能会对个体的健康造成多种有害影响。该提案旨在表征异生素和视黄酸代谢 CYP26 酶之间的相互作用，这些酶会改变视黄酸代谢和清除并可能导致不良影响。

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.