Regulation of cytochrome P4501A1 expression by hyperoxia in human lung cell lines: Implications for hyperoxic lung injury.

Toxicol Appl Pharmacol 2008 Dec 11;233(2):169-78. Epub 2008 Sep 11.

Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, Texas, USA.

Supplemental oxygen, used to treat pulmonary insufficiency in newborns, contributes to the development of bronchopulmonary dysplasia (BPD). Cytochrome P4501A enzymes are induced by hyperoxia in animal models, but their role in human systems is unknown. Here we investigated the molecular mechanisms of induction of CYP1A1 by hyperoxia in human lung cell lines. Three human lung cell lines were exposed to hyperoxia (95% O2) for 0-72 h, and CYP1A1 activities, apoprotein contents, and mRNA levels were determined. Hyperoxia significantly induced CYP1A1 activity and protein contents (2-4 fold), and mRNA levels (30-40 fold) over control in each cell line. Transfection of a CYP1A1 promoter/luciferase reporter construct, followed by hyperoxia (4-72 h), showed marked (2-6 fold) induction of luciferase expression. EMSA and siRNA experiments strongly suggest that the Ah receptor (AHR) is involved in the hyperoxic induction of CYP1A1. MTT reduction assays showed attenuation of cell injury with the CYP1A1 inducer beta-naphthoflavone (BNF). Our results strongly suggest that hyperoxia transcriptionally activates CYP1A1 expression in human lung cell lines by AHR-dependent mechanisms, and that CYP1A1 induction is associated with decreased toxicity. This novel finding of induction of CYP1A1 in the absence of exogenous AHR ligands could lead to novel interventions in the treatment of BPD.

Download full-text PDF

Source
http://linkinghub.elsevier.com/retrieve/pii/S0041008X0800366
Publisher Site
http://dx.doi.org/10.1016/j.taap.2008.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646384PMC
December 2008

Publication Analysis

Top Keywords

cell lines
16
human lung
16
lung cell
16
induction cyp1a1
12
cyp1a1
9
hyperoxia human
8
mrna levels
8
hyperoxia
7
cell
6
lung
5
induction
5
human
5
activity protein
4
protein contents
4
cyp1a1 activity
4
hyperoxia induced
4
induced cyp1a1
4
expression human
4
lines ahr-dependent
4
cyp1a1 expression
4

Altmetric Statistics

Similar Publications