Cytochrome P450 3A expression and function in liver and intestinal mucosa from dexamethasone-treated sheep

MATÉ L; LIFSCHITZ, A.; SALLOVITZ J,; BALLENT M,; MUSCHER, A.; WILKENS, M.; SCHRODER, B; LANUSSE, C; VIRKEL G.

JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2012 vol. 35 p. 319 - 328

0140-7783

The effects of repeated administrations of dexamethasone (DEX) (3 mg⁄ kg ⁄ day by IM 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 (RXRa) 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 CYP3Adependent 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 RXRa. 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.