P450 Metabolism of Glucocorticoids in Lungs of Pediatric Asthmatics

P450 小儿哮喘患者肺部糖皮质激素的代谢

• 批准号: 7760817
• 负责人: Garold S Yost
• 金额: $ 46.31万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760817
• 关键词: A549; Address; Adolescent; Adverse effects; Age; Aptitude; Archives; Asthma; Beclomethasone Dipropionate; Biochemical; Blood specimen; Breathing; Budesonide; CYP3A4 gene; CYP3A5 gene; Cell Line; Cell Respiration; Cells; Chemicals; Child; Childhood; Childhood Asthma; Clinical; Cytochrome P450; DNA; Deglutition; Development; Enzymes; Epithelial; Epithelial Cells; Flunisolide; Fluticasone propionate; Frequencies; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Glucocorticoids; Goals; Growth; Haplotypes; Hepatic; Hepatocyte; Hospitalization; Human; Human Cell Line; Hypersensitivity; In Situ; In Vitro; Incidence; Individual; Inflammatory; Inhalation Therapy; Kinetics; Knowledge; Lead; Liver; Lung; Measures; Mechanical ventilation; Medicine; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methods; Modality; Modern Medicine; Newborn Infant; Organ; Parents; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Population; Process; Production; Proteins; Recording of previous events; Relative (related person); Research; Resistance; Sampling; Severities; Source; Staging; Steroids; Structure; Suction; Symptoms; Therapeutic; Transcript; Triamcinolone; Western Blotting; asthmatic patient; base; catalyst; cohort; effective therapy; improved; liquid chromatography mass spectrometry; mortality; novel; oxidation; public health relevance; respiratory; response; selective expression; steroid metabolism; tumorigenic

DESCRIPTION (provided by applicant): A major therapeutic challenge of modern medicine is the ever-increasing incidence of asthma in children during the past several decades. However, one significant therapeutic modality that has provided considerable progress is the use of inhaled glucocorticoids (GC) that target the inflammatory component of asthma while minimizing systemic GC adverse effects. These drugs provide considerable reduction in mortality and in incidence and severity of asthma symptoms, but estimates of resistance to GCs are as high as 50% of the pediatric asthmatic population. As much as 90% of inhaled GCs are swallowed and absorbed, but systemic effects are minimized through first pass hepatic metabolism. Presumably, inhaled GCs act locally within the lung where their concentrations are highest and are then metabolized by cytochrome P450 enzymes in situ. The three major CYP3A enzymes (3A4, 3A5, 3A7) are the primary catalysts of GC oxidation in human liver, where much is known about the ontogeny and developmental expression of the enzymes. However, essentially nothing is known about the relative levels of CYP3A expression in lungs of children, or the developmental changes during childhood in the important respiratory cells where GC drugs act and undergo oxidative metabolism. The exact chemical pathways catalyzed by the CYP 3A enzymes in the metabolism of GCs are also not known. Genetic polymorphisms, organ-selective expression, and autoinduction of the CYP3A genes are known mechanisms that predict dramatic interindividual metabolic diversity, resulting in resistance or hypersensitivity to GCs. None of these processes has been studied in asthmatic children. The major long-term goal of this research is to significantly improve GC therapy in asthmatic children, and the hypothesis of this application is resistance or hypersensitivity to inhaled GCs in pediatric asthmatics is predominantly controlled by developmental expression patterns, genetic polymorphisms, and environmental responsiveness of P450 3A genes. We will address this hypothesis with the following specific aims: 1) characterize the metabolites and metabolic pathways of the five most frequently used, therapeutically relevant GCs by each of the three major CYP3A enzymes; 2) evaluate the induction of the 3A genes in lung and liver cells; 3) correlate GC-induced P450 3A transcripts to increased metabolism of the steroids and establish developmental patterns of P450 3A gene expression in pediatric pulmonary cells from tracheal suctioning samples; and 4) correlate CYP3A5 and CYP3A7 polymorphisms with GC resistance or hypersensitivity from a cohort of pediatric asthma patients. The results of this experimental plan will provide essential information on the basic genetic and biochemical factors that lead to effective GC therapy. This knowledge can be used with genotype analysis to guide the clinical choice of GC products, and provide a more robust rationale for alternative asthmatic treatment modalities. PUBLIC HEALTH RELEVANCE: Inhaled glucocorticoid medicines (GC) provide effective therapy for children with asthma, but as many as 50% of children with asthma are not helped by inhaled GCs, i.e. they are resistant to these medicines. Essentially nothing is known about the relative levels of P450 enzyme expression in lungs of children, or the developmental changes during childhood in the important respiratory cells where GC agents act and are cleared. The major long-term goal of this research is to significantly improve GC therapy in asthmatic children.

描述（由申请人提供）：现代医学的一个主要治疗挑战是过去几十年来儿童哮喘发病率不断增加。然而，一种取得了相当大进展的重要治疗方式是使用吸入性糖皮质激素（GC），它针对哮喘的炎症成分，同时最大限度地减少全身性糖皮质激素的不良反应。这些药物可显着降低死亡率以及哮喘症状的发生率和严重程度，但估计儿童哮喘人群对 GC 的耐药性高达 50%。多达 90% 的吸入 GC 被吞咽和吸收，但通过首过肝脏代谢将全身影响降至最低。据推测，吸入的 GC 在肺部局部发挥作用，其浓度最高，然后被细胞色素 P450 酶原位代谢。三种主要的 CYP3A 酶（3A4、3A5、3A7）是人类肝脏中 GC 氧化的主要催化剂，人们对这些酶的个体发育和发育表达了解很多。然而，对于儿童肺部 CYP3A 表达的相对水平，或者 GC 药物在其中发挥作用并进行氧化代谢的重要呼吸细胞在儿童时期的发育变化，基本上一无所知。 GC 代谢中 CYP 3A 酶催化的确切化学途径也是未知的。 CYP3A 基因的遗传多态性、器官选择性表达和自诱导是已知的机制，可预测显着的个体间代谢多样性，从而导致对 GC 的抵抗或过敏。这些过程都没有在哮喘儿童中进行过研究。这项研究的主要长期目标是显着改善哮喘儿童的GC治疗，该应用的假设是小儿哮喘患者对吸入GC的耐药性或过敏性主要受发育表达模式、遗传多态性和环境反应性控制。 P450 3A 基因。我们将通过以下具体目标来解决这一假设：1）通过三种主要 CYP3A 酶中的每一种来表征五种最常用的、治疗相关的 GC 的代谢物和代谢途径； 2)评估3A基因在肺和肝细胞中的诱导作用； 3) 将GC诱导的P450 3A转录本与类固醇代谢增加相关联，并建立来自气管抽吸样本的小儿肺细胞中P450 3A基因表达的发育模式； 4) 将 CYP3A5 和 CYP3A7 多态性与一组儿科哮喘患者的 GC 耐药性或超敏反应相关联。该实验计划的结果将提供有关导致有效 GC 治疗的基本遗传和生化因素的重要信息。这些知识可与基因型分析结合使用，指导 GC 产品的临床选择，并为替代哮喘治疗方式提供更强有力的理由。 公共卫生相关性：吸入糖皮质激素药物 (GC) 为哮喘儿童提供有效的治疗，但多达 50% 的哮喘儿童无法通过吸入 GC 获得帮助，即他们对这些药物产生耐药性。对于儿童肺部 P450 酶表达的相对水平，或者 GC 制剂作用和清除的重要呼吸细胞在儿童时期的发育变化，基本上一无所知。这项研究的主要长期目标是显着改善哮喘儿童的GC治疗。