Cytochrome P450 Gene Regulation in Lung

描述（由申请人提供）：人类暴露于各种各样的气体毒性或致癌化学物质，这些化学物质在细胞色素P450酶使母体化合物生物活化后发挥其毒性。肺部疾病引起显著的发病率和死亡率，特异性P450酶有助于许多这些疾病的病因学。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，在肝脏或其他组织中不同时表达。不同个体对某些P450基因变异的肺特异性表达也可能导致人类对肺毒物的不同易感性，但其分子机制尚不清楚。本研究的假设是，人类肺上皮细胞中某些细胞色素P450基因的选择性表达是由独特的、以前未表征的转录因子驱动的；这些因素共同调节CYP2F1、CYP2S1、CYP3A5和CYP4B1基因的表达”，这些基因的遗传变异将导致不同的易感性。本研究的主要长期目标是精确确定肺细胞中调节P450基因表达的因素。这一目标将通过以下目标实现：1)鉴定肺选择性P450基因的共享和独特启动子元件，并通过从人肺组织和细胞中结合这些核心元件的反式作用核因子来确定功能性转录控制；2)鉴定和表征被鉴定为CYP2F1关键调节因子的肺特异性因子（LSF），以及与其他肺选择性P450基因形成转录复合物的潜在共调节因子和其他相关核蛋白；3)通过评估细胞在诱导和过度表达野生型基因、已确定的遗传变异和/或特定反式作用因子后对肺毒物的易感性，证明P450基因表达在工程细胞中的功能重要性；4)鉴定并验证可能影响受试者间肺毒性变异的2F1和2S1遗传变异。这些研究将为控制肺细胞中P450基因表达的特定机制提供重要的、独特的见解，并将对由细胞色素P450酶的毒性生物激活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.