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）：现代医学的主要治疗挑战是过去几十年来儿童哮喘的发生率不断增加。然而，一种取得了相当大进步的重要治疗方式是使用吸入的糖皮质激素（GC），该糖皮质激素（GC）靶向哮喘的炎症成分，同时最大程度地减少全身性GC不良反应。这些药物可显着降低死亡率，哮喘症状的发病率和严重程度，但对GC的耐药性的估计高达儿科哮喘人群的50％。多达90％的吸入GC被吞咽和吸收，但是通过首次通过肝代谢将全身性效应最小化。据推测，吸入的GC在其浓度最高的肺部局部起作用，然后被细胞色素P450酶代谢。三种主要的CYP3A酶（3A4，3A5，3A7）是人肝脏中GC氧化的主要催化剂，在该酶的本体发育和发育表达中众所周知。但是，基本上，儿童肺中CYP3A表达的相对水平，或者在GC药物起作用并经历氧化代谢的重要呼吸细胞中，儿童期的发育变化尚无知之甚少。 GCS代谢中CYP 3A酶催化的确切化学途径也不知道。 CYP3A基因的遗传多态性，器官选择性表达和自动诱导是预测戏剧性的个体间代谢多样性的已知机制，从而导致对GC的耐药性或超敏反应。这些过程都没有在哮喘儿童中进行研究。这项研究的主要长期目标是显着改善哮喘儿童的GC疗法，并且该应用的假设是对儿科哮喘的吸入GC的抵抗力或超敏反应主要由发育表达模式，遗传多态性和P450 3A基因的环境响应能力。我们将以以下具体目的解决这一假设：1）表征五种最常用的，与三种主要CYP3A酶中每种最常用的，治疗相关的GC的代谢物和代谢途径； 2）评估肺和肝细胞中3A基因的诱导； 3）将GC诱导的P450 3A转录本与类固醇的代谢增加相关，并在来自气管吸力样品的小儿肺细胞中建立P450 3A基因表达的发育模式；和4）将CYP3A5和CYP3A7多态性与GC耐药性或小儿哮喘患者队列的超敏反应相关联。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。这些知识可以与基因型分析一起使用，以指导GC产品的临床选择，并为替代性哮喘治疗方式提供更强大的理由。 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％的哮喘儿童没有吸入GC的帮助，即他们对这些药物具有抵抗力。基本上，对于儿童肺中P450酶表达的相对水平或儿童期在GC剂作用并清除的重要呼吸细胞中，儿童期的发育变化一无所知。这项研究的主要长期目标是显着改善哮喘儿童的GC疗法。