Cytrochrome P45 2S1 gene regulation in human lung epithelial cells

University Of Utah, Salt Lake City UT

Investigators

Abstract

[unreadable] 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. Additionally, metabolism by P450s is critical for maintaining the proper physiological levels of endogenous substrates. The selective response elicited in lung tissue by the presence of exogenous or endogenous compounds is primarily related to the selective expression and regulation of P450 genes in bronchiolar or alveolar epithelial cells, without concomitant expression in liver or other tissues. The hypothesis of this research is that the selective expression of the cvtochrome P450 2S1 (CYP2S1) gene in human lung epithelial cells is driven by unique, previously uncharacterized transcription factors; these factors act in concert to regulate its expression: and that regulated expression of CYP2S1 is an important mechanism for retinoic acid metabolism in lung epithelial cells. The major goal of this research is to precisely determine the factors that regulate CYP2S1 gene expression in lung cells and establish a role for CYP2S1 regulation of retinoic acid metabolism in lung epithelial cells. This goal will be realized through the following objectives: 1) identify unique promoter elements of the lung-selective P450 2S1 gene that defines functional transcriptional control by frans-acting nuclear factors from human lung tissues and cells that bind these core elements; 2) identify promoter elements and frans-acting nuclear factors involved in retinoic-acid mediated CYP2S1 gene induction; and to explore the contribution of CYP2S1 gene induction in the regulation of retinoic acid and its metabolites within the lung. Relevance: Lung diseases cause significant morbidity and mortality, and specific metabolic enzymes (P450s) contribute to the etiology of many of these diseases. These studies will provide vital, unique insight concerning the specific mechanisms that control expression of a recently identified P450 gene in lung cells and may provide significant insight into the tissue-selective metabolism and regulation of Vitamin A. [unreadable] [unreadable] [unreadable] [unreadable]