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 6b-hydroxylase, _44.60% and _18.07%; testosterone 2b-hydroxylase, _43.95% and _11.69%); by contrast, an increase (about 2-fold) of the urinary 6b-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 6b-hydroxycortisol:cortisol ratio is not useful to monitor in vivo CYP3A activity in DEX-treated individuals.

Effects of dexamethasone, administered for growth-promoting purposes, upon the hepatic cytochrome P4503A expression in the veal calf

CANTIELLO, Michela;CARLETTI, Monica;BOLLO, Enrico;NEBBIA, Carlo;DACASTO, Mauro
2009

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 6b-hydroxylase, _44.60% and _18.07%; testosterone 2b-hydroxylase, _43.95% and _11.69%); by contrast, an increase (about 2-fold) of the urinary 6b-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 6b-hydroxycortisol:cortisol ratio is not useful to monitor in vivo CYP3A activity in DEX-treated individuals.
77
451
463
http://www.elsevier.com/locate/tvjl
cattle; dexamethasone; liver; CYP3A; illicit treatment; nuclear receptors
Cantiello M; Giantin M; Carletti M; Lopparelli RM; Capolongo F; Lasserre F; Bollo E; Nebbia C; Martin PGP; Pineau T; Dacasto M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/99826
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