title: Cytochrome P450 3A expression and function in liver and intestinal mucosa from dexamethasone-treated sheep.
abstract: The effects of repeated administrations of dexamethasone (DEX) (3 mg/kg/day by i.m. route for 7 days) on the gene expression profile of a cytochrome P450 (CYP) 3A28-like isoenzyme, on the expression of a CYP3A-immunoreactive protein and on CYP3A-dependent metabolic activities in sheep liver and small intestinal mucosa were evaluated in the current work. CYP 3A-dependent metabolic activities (erythromycin and triacetyl-oleandomycin N-demethylations) were assessed in microsomal fractions. The mRNA expression of CYP3A28-like, glucocorticoid receptor, constitutive androstane receptor, pregnane X receptor and retinoic X receptor alpha (RXRα) was determined by quantitative real-time PCR. The expression of a CYP3A-immunoreactive protein was measured by Western blot analyses. In the liver, DEX treatment increased CYP3A28-like mRNA levels (2.67-fold, P<0.01) and CYP3A apoprotein expression (1.34-fold, P<0.05) and stimulated CYP3A-dependent metabolism. High and significant correlation coefficients between CYP3A-dependent activities and CYP3A28-like gene (r=0.835-0.856, P<0.01) or protein (r=0.728-0.855, P<0.05) expression profiles were observed. Among the transcriptional factors, DEX only stimulated (2.1-fold, P<0.01) the mRNA expression of RXRα. In sheep small intestine, DEX caused a slight increment (34.6%, P<0.05) in erythromycin N-demethylase activity in the jejunal mucosa and a significant enhancement (P<0.05) of CYP3A apoprotein level in the duodenal mucosa.
authors: Laboratory of Veterinary Pharmacology, Faculty of Veterinary Sciences, UNCPBA, Tandil, Argentina.
authors: M L
authors: ML
authors: Maté
authors: A
authors: A
authors: Lifschitz
authors: J
authors: J
authors: Sallovitz
authors: M
authors: M
authors: Ballent
authors: A S
authors: AS
authors: Muscher
authors: M R
authors: MR
authors: Wilkens
authors: B
authors: B
authors: Schröder
authors: C
authors: C
authors: Lanusse
authors: G
authors: G
authors: Virkel
mesh_terms: D000818:Animals; D015415:Biomarkers; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel / Q000662:veterinary; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D012313:RNA / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012756:Sheep / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D012313:RNA; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A