Cytochrome P450 Gene Regulation in Lung

描述(由申请人提供)：人类暴露在多种有毒或致癌的化学物质中，这些化学物质在母化合物被细胞色素P450酶激活后产生毒性。肺部疾病导致显著的发病率和死亡率，而特定的P450酶导致了其中许多疾病的病因学。对肺组织的选择性毒性主要与P450基因在细支气管或肺泡上皮细胞中的选择性表达有关，而在肝脏或其他组织中不伴随表达。也有可能是不同个体对某些P450基因变异的肺特异表达导致了人类对气体毒物的不同易感性，但相关的分子机制尚不清楚。这项研究的假设是，某些细胞色素P450基因在人肺上皮细胞中的选择性表达是由独特的、以前未确定的转录因子驱动的；这些因子协同作用，调节CYP2F1、CYP2S1、CYP3A5和CYP4B1基因的表达，“这些基因中的遗传变异将有助于差异易感性。这项研究的主要长期目标是精确确定调节肺细胞中P450基因表达的因素。这一目标将通过以下目标来实现：1)确定肺选择性P450基因共有的和独特的启动子元件，并通过反式作用于人肺组织和结合这些核心元件的细胞的核因子来确定功能转录调控；2)鉴定被确定为CYP2F1关键调节因子的肺特异因子(LSF)，以及潜在的协同调节因子和与其他肺选择性P450基因形成转录复合体的其他相关核蛋白；3)通过野生型基因的诱导和过度表达后细胞对肺毒物敏感性的评估、已确定的基因变体和/或特定的反式作用因子来证明P450基因在工程细胞中表达的功能重要性；4)识别和验证2F1和2S1基因变体，这些基因变体可能影响肺毒性的主体间变异性。这些研究将为控制肺细胞中P450基因表达的具体机制提供重要而独特的见解，并将对由细胞色素P450酶激活的有毒生物引起或加剧的人类肺部疾病产生重大影响。

DESCRIPTION (provided by applicant): Humans are exposed to a large variety of pneumotoxic or carcinogenic chemicals that exert their toxicities after bioactivation of the parent compound by cytochrome P450 enzymes. Lung diseases cause significant morbidity and mortality, and specific P450 enzymes contribute to the etiology of many of these diseases. The selective toxicity to lung tissues is primarily related to the selective expression of P450 genes in bronchiolar or alveolar epithelial cells, without concomitant expression in liver or other tissues. It is also likely that lung-specific expression of certain P450 genetic variants by different individuals leads to differential human susceptibilities to pneumotoxicants, but the molecular mechanisms responsible are not known. The hypothesis of this research is that the selective expression of certain cytochrome P450 genes in human lung epithelial cells is driven by unique, previously uncharacterized transcription factors; these factors act in concert to regulate the expression of the CYP2F1, CYP2S1, CYP3A5, and CYP4B1 genes," and that genetic variability in these genes will contribute to differential susceptibility. The major long-term goal of this research is to precisely determine the factors that regulate the expression of P450 genes in lung cells. This goal will be realized through the following objectives: 1) identify the shared and unique promoter elements of the lung-selective P450 genes and define functional transcriptional control by trans-acting nuclear factors from human lung tissues and cells that bind these core elements; 2) identify and characterize the lung-specific factor (LSF) identified as a CYP2F1 key regulator, along with potential co-regulatory factors and additional related nuclear proteins that form transcriptional complexes with the other lung-selective P450 genes; 3) to demonstrate the functional importance of P450 gene expression in engineered cells through assessment of cellular susceptibility to pneumotoxicants after induction and overexpression of the wild type genes, identified genetic variants, and/or specific trans-acting factors; 4) identify and validate 2F1 and 2S1 genetic variants that may influence intersubject variability to lung toxicities. These studies will provide vital, unique insight concerning the specific mechanisms that control expression of P450 genes in lung cells and will have significant impact on human lung diseases that are caused or exacerbated by toxicant bioactivation by cytochrome P450 enzymes.