Regulation of pulmonary and hepatic cytochrome P4501A expression in the rat by hyperoxia: implications for hyperoxic lung injury.
In order to characterize the response of various pulmonary cell types to polycyclic aromatic hydrocarbons, the expression of cytochrome P450 (CYP) 1A1 and 2B1 mRNA in the lung of rats, with or without induction by 3-methylcholanthrene (3MC), was analyzed by in situ hybridization using appropriate 35S-labeled riboprobes. The expression of the corresponding proteins was investigated immunohistochemically. Following induction with 3MC, the kinetics of mRNA expression differed considerably between Clara cells and type II pneumocytes and venous endothelial cells. In Clara cells, mRNA expression was detected as early as 1 h after induction, peaked between 2 and 4 h, and was completely undetectable at 14 h. In contrast, venous endothelial cells and type II pneumocytes exhibited permanent mRNA expression of CYP 1A1 in 3MC-pretreated rats. These kinetic results explain the striking absence of correlation between mRNA and protein expression observed in Clara cells 24 h after the end of the induction protocol, as these cells exhibited intense protein expression with no mRNA. In contrast, a good correlation was observed for mRNA and protein expression of CYP 2B1, with similar expressions for Clara cells and type II pneumocytes, but no expression in endothelial cells. This study clearly distinguished the regulation of CYP 1A1 expression in the rat lung from that described in the liver. The differences observed in the various lung cell types, whatever the post-transcriptional mechanisms involved, emphasize that studies must be performed at the cellular level in order to understand the specific response to xenobiotics, not only of this organ as a whole but also of its various anatomic structures.