Increased expression and decreased activity of cytochrome P450 1A1 in a murine model of toluene diisocyanate-induced asthma

In the lung, cytochromes P450 (CYP) may be affected by inhaled pollutants. In a previous study, we showed that acute inhalation of toluene diisocyanate (TDI), a low molecular weight chemical known to cause occupational asthma, decreased CYP2Bl expression in rat lung. In the present work, we investigated the effect of TDI in a murine model of TDI-induced asthma. Mice were skin-sensitized with TDI on 2 consecutive days and challenged intranasally 8 days later. Lung expression and activity of CYP were assessed 24 h after the challenge. A significant increase in Cyplal protein expression was detected by western blotting in lung from mice sensitized and challenged with TDI, whereas no modification of expression of other CYP, namely Cyp2b, Cyp2el and Cyp3a was observed. Increase in Cyplal protein was associated with an increase in Cyplal mRNA, as assessed by polymerase chain reaction after reverse transcription of total lung RNA. However, a decreased Cyplal activity, as measured by O-deethylation of ethoxyresorufin was observed in lung from TDI-sensitized and challenged mice, suggesting that TDI may inhibit Cyplal function. In agreement with this hypothesis, in vitro experiments conducted on liver microsomes overexpressing Cyplal after treatment of mice with 3-methylcholanthrene showed that TDI markedly inhibited in a concentration-dependent manner Cyplal activity. In conclusion, expression of Cyplal, known to exhibit rather negative functions in the lung, is increased in mice sensitized and challenged with TDI. However, this effect is associated with a decreased enzyme activity, which might limit the toxicological consequences of increased Cyplal expression.