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

MATÉ M. L., LIFSCHITZ A.,SALLOVITZ J.,BALLENT M.,MUSCHER A.,WILKENS M.,SCHRÖDER 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, 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. Cytochrome P450 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 were 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) and CYP3A apoprotein expression (1.34-fold), and stimulated CYP3A-dependent metabolism. High and significant correlation coefficients between CYP3A-dependent activities and CYP3A28-like gene (r= 0.835 - 0.856) or protein (r= 0.728 - 0.855) expression profiles were observed. Among the transcriptional factors, DEX only stimulated (2.1-fold) the mRNA expression of retinoic X receptor alpha. In sheep small intestine, DEX caused a slight increment (34.6%) of erythromycin N-demethylase activity in the jejunal mucosa and a significant enhancement of CYP3A apoprotein level in the duodenal mucosa.