Expression of cytochromes P450 3A in mouse lung: effects of dexamethasone and pregnenolone 16alpha-carbonitrile.
Expression of cytochromes P450 3A (CYP3A) has been reported in the lung, but its regulation has received little attention. In the present study, we assessed lung levels of Cyp3a mRNA, protein and activity in control mice and in mice treated with either dexamethasone (DEX), pregnenolone 16alpha-carbonitrile (PCN) or a mixture of DEX+PCN. Lung expression of the pregnane X receptor (PXR) was also investigated. Constitutive levels of Cyp3a mRNA were found in the lung from control mice by polymerase chain reaction after reverse transcription of total RNA (RT-PCR). These levels were significantly increased (2.0-fold, P<0.05) in mice treated with DEX and further enhanced (2.7-fold increase, P<0.01) in mice treated with DEX+PCN. In control mice, basal levels of Cyp3a protein and activity were also found, as assessed by western blot and measure of testosterone 6beta-hydroxylation, respectively. In mice treated with DEX or DEX+PCN, changes in Cyp3a protein and activity exhibited the same pattern as those in Cyp3a mRNA. In contrast, PCN alone failed to trigger consistent increases in lung Cyp3a mRNA, protein and activity. PXR mRNA was not detected in the lung from control or PCN-treated mice by RT-PCR, but was found at significant levels in the lungs from mice treated with DEX or DEX+PCN. Our results show that expression of Cyp3a is upregulated by glucocorticoids in mouse lung, and that this effect is potentiated by antiglucocorticoids. This potentiation may involve PXR, expression of which is induced in the lung of glucocorticoid-treated mice.
Haag
Muriel
M
Inserm U425, Neuroimmunopharmacologie pulmonaire, Faculté de Pharmacie, Université Louis Pasteur Strasbourg-I, 74 Route du Rhin, BP 2467401, Illkirch cedex, France..
Fautrel
Alain
A
Guillouzo
André
A
Frossard
Nelly
N
Pons
Françoise
F
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000235:genetics; D011285:Pregnenolone Carbonitrile / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D011285:Pregnenolone Carbonitrile; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating