title: Increased expression and decreased activity of cytochrome P450 1A1 in a murine model of toluene diisocyanate-induced asthma.
abstract: 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 CYP2B1 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 Cyp1a1 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, Cyp2e1 and Cyp3a was observed. Increase in Cyp1a1 protein was associated with an increase in Cyp1a1 mRNA, as assessed by polymerase chain reaction after reverse transcription of total lung RNA. However, a decreased Cyp1a1 activity, as measured by O-deethylation of ethoxyresorufin was observed in lung from TDI-sensitized and challenged mice, suggesting that TDI may inhibit Cyp1a1 function. In agreement with this hypothesis, in vitro experiments conducted on liver microsomes overexpressing Cyp1a1 after treatment of mice with 3-methylcholanthrene showed that TDI markedly inhibited in a concentration-dependent manner Cyp1a1 activity. In conclusion, expression of Cyp1a1, 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 Cyp1a1 expression.
authors.affiliation: Inserm U425, Neuroimmunopharmacologie pulmonaire, Faculté de Pharmacie, Université Louis Pasteur-Strasbourg-I, BP 24, 67401 Illkirch Cedex, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Haag
authors.forename: Thea
authors.initials: T
authors.lastname: Leusink-Muis
authors.forename: Renaud
authors.initials: R
authors.lastname: Le Bouquin
authors.forename: Frans P
authors.initials: FP
authors.lastname: Nijkamp
authors.forename: Alain
authors.initials: A
authors.lastname: Lugnier
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.forename: Françoise
authors.initials: F
authors.lastname: Pons
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced* / Q000201:enzymology; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity*
chemical_list: D012333:RNA, Messenger; D014051:Toluene 2,4-Diisocyanate; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1