Altered expression of lung cytochrome P450 3A1 in rat after exposure to sulfur mustard.
Expression of cytochromes P450 (CYP) and glutathione S-transferases in the lung may be affected by inhaled pollutants. We have investigated the effect of sulfur mustard on the expression of CYP 1A1, 2B1, 2E1 and 3A1, as well as of alpha-, micro- and pi-glutathione S-transferases in rat lung. Sulfur mustard (0.025, 0.05 or 0.1 mg/kg) or its vehicle was administered to anaesthetized animals by intratracheal injection. Expression of CYP and glutathione S-transferases was analysed 24 hr after administration of the vesicant warfare using western blotting. Preservation of airway epithelium integrity after animal exposure to sulfur mustard was confirmed by histological examination of tracheal and lung tissues from control and treated animals. Constitutive levels of CYP 2B1 and 3A1 proteins were found in lung tissue from control rats, whereas CYP 1A1 and 2E1 proteins were not detected. Animal exposure to sulfur mustard enhanced CYP 3A1 protein levels by 80 to 103%. In contrast, exposure to sulfur mustard neither modified CYP 2B1 expression, nor led to detectable expression of CYP 1A1 or 2E1. Constitutive levels of alpha-, micro- and pi-glutathione S-transferase proteins were found in lung tissue from control rats. Exposure to sulfur mustard had no effect on expression of either of the glutathione S-transferases. Our results show that intratracheal exposure to sulfur mustard selectively increases CYP 3A1 expression in rat lung. Taking into account the major role of CYP of the 3A family in the metabolism of drugs, up-regulation of CYP 3A1 by sulfur mustard might have important therapeutic consequences.
Pons
F
F
INSERM U425, Faculty of Pharmacy, lllkirch, France. pons@pharma.u-strasbg.fr
Calvet
J H
JH
Haag
M
M
Raeppel
V
V
Keravis
T
T
Frossard
N
N
D000818:Animals; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D005982:Glutathione Transferase / Q000378:metabolism; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009151:Mustard Gas / Q000032:analysis / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology; D014132:Trachea / Q000187:drug effects / Q000473:pathology; D015854:Up-Regulation
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D005982:Glutathione Transferase; D009151:Mustard Gas