Effects of Xenobiotics on CYP26 Activity and Retinoic Acid Homeostasis

异生素对 CYP26 活性和视黄酸稳态的影响

基本信息

批准号：
7585283
负责人：
Nina Isoherranen
金额：
$ 28.65万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-10 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7585283
关键词：
Active Sites Adult Adverse effects Affect Affinity Antiepileptic Agents Apoptosis Applications Grants Binding Biochemical Biodegradation Biological Biological Process Biopsy Birth Blood CYP26B1 gene Cell Line Cell division Cells Cessation of life Characteristics Childhood Clinical Research Competence Cytochrome P450 Defect Development Disease Embryonic and Fetal Development Enzyme Inhibition Enzyme Interaction Enzyme Kinetics Enzymes Epithelial Epithelium Family Feedback Fetal Development Gene Expression Regulation Genetic Transcription Goals Health Hepatocyte Homeostasis Human Immune Immunity In Vitro Individual Intestines Isoenzymes Ketoconazole Kinetics Knockout Mice Knowledge Lead Life Ligands Liver Maintenance Malignant Neoplasms Mediating Messenger RNA Metabolism Mixed Function Oxygenases Pharmaceutical Preparations Placentation Plasma Play Pregnancy Process Protein Isoforms Public Health Recombinants Regulation Reproduction Retinoids Role Substrate Specificity Testing Tissues Titrations Transcript Tretinoin Vitamin A Vitamin A Deficiency Xenobiotic Metabolism Xenobiotics base bone health bone loss cancer prevention cell growth regulation design enzyme activity fetal human tissue improved in vivo inhibitor/antagonist malformation retinoic acid 4-hydroxylase tool

项目摘要

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.

描述（由申请人提供）：该提案的长期目标是确定异种生物和CYP26酶之间的相互作用，从而导致血浆和不同组织中的全反式视黄酸（RA）浓度改变。这很重要，因为对RA浓度的准确控制对于繁殖，胎儿和胎盘发育，维持上皮的维持，免疫和凋亡的调节以及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的健康造成多重有害影响。该赠款提案的中心假设是CYP26酶调节循环RA浓度并控制体内RA的清除率。该假设将通过旨在提供CYP26A1和CYP26B1在调节RA稳态中的作用的三个特定目的进行检验。该提案的第一个具体目的是证明CYP26A1和CYP26B1是成人人体组织中的主要RA羟化酶。第二个具体目的是鉴定CYP26A1和CYP26B1的异种和内源性配体。 AIM 3将测试选定的异种生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理解，这是两个研究的P450酶。细胞视黄酸浓度的严格调节对于正常繁殖，免疫能力，健康上皮和骨骼健康的维持以及细胞凋亡和细胞分裂的调节至关重要。因此，控制细胞视黄酸代谢的过程的改变会对个人的健康造成多种不利影响。该建议旨在表征异种生物和视黄酸代谢CYP26酶之间的相互作用，这些酶改变了视黄酸代谢和清除率，并可能导致不良反应。