Effects of dexamethasone, administered for growth promoting purposes, upon the hepatic cytochrome P450 3A expression in the veal calf

Abstract

Dexamethasone (DEX) exerts its known anti-inflammatory and immunosuppressant activities through the interaction with the glucocorticoid receptor (GR). In human liver, DEX is metabolized by cytochrome P450 3A (CYP3A); moreover, it is among those xenobiotics which induce CYP3A itself. The transcriptional regulation of CYP3A involves GR and nuclear receptors (NRs). In cattle, DEX is used at low dosages as a growth promoter; besides, CYP3A is expressed in the liver. In the present study, the effects of two illicit DEX protocols upon liver CYP3A were investigated in the veal calf. Dexamethasone, administered per os (DOS) or injected intramuscularly (DIM) at growth promoting purposes, increased GR mRNA (+25.62% and +73.02% of CTRL for DOS and DIM, respectively), while tyrosine aminotransferase (TAT) and NRs gene expression profiles were unaffected; decreased CYP3A mRNA (−20.64% and −16.07% with Q RT-PCR; −30.55% and −34.31% with Northern blotting); at the post-translational level, decreased TAT activity (−19.84% and 44.34%), CYP3A apoprotein (−27.65% and −42.85%) and CYP3A-dependent enzyme activities (erythromycin N-demethylase, −78.89% and −23.87%; ethylmorphine N-demethylase, −44.26% and −28.37%; testosterone 6β-hydroxylase, −44.60% and −18.07%; testosterone 2β-hydroxylase, −43.95% and −11.69%); by contrast, an increase (about 2-fold) of the urinary 6β-hydroxycortisol:cortisol ratio was observed in vivo. In summary, DEX modulates cattle liver CYP3A at pre- and post-translational level. Species-differences in GR–NRs–CYP3A regulation and in their response to differing DEX dosages might justify present results. Furthermore, the urinary 6β-hydroxycortisol:cortisol ratio is not useful to monitor in vivo CYP3A activity in DEX-treated individuals.