Influence of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on expression of P-glycoprotein and cytochrome P450 3A in sheep

WILKENS M.; MATÉ L.; SCHNEPEL N; KLINGER C.; MUSCHER A.; BALLENT M.; LIFSCHITZ A.

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2015

0960-0760

In order to improve calcium and phosphorus balance, beef cattle and dairy cows can be supplementedwith vitamin D. However, different vitamin D metabolites have been shown to increase expression of Pglycoprotein(P-gp, MDR1, ABCB1) and cytochrome P450 3A (CYP3A) in rodents as well as in cell culturesystems. As such interferences might have an impact on pharmacokinetics of some drugs widely-used inveterinary medicine, we investigated the expression of P-gp, CYP3A, vitamin D receptor (VDR), pregnaneX receptor (PXR) and retinoid X receptor a (RXRa) in sheep either treated orally with 6 mg/kg bodyweight (BW) 25-hydroxyvitamin D3 (OHD3) for ten days before sacrifice or 12 h after intravenousinjection of 0.5 mg/kg BW 1,25-dihydroxyvitamin D3 (1,25- (OH)2D3). Down-regulation of ruminal,jejunal and hepatic, but not renal P-gp could be found with 25-OHD3 supplementation. Interestingly, thiseffect on P-gp was not observed in tissues from 1,25-(OH)2D3-treated sheep. In contrast, 1,25-(OH)2D3 induced a significant up-regulation of renal and jejunal CYP3A expression, while 25-OHD3 had noimpact. Renal expression of VDR and PXR was also increased by treatment with 1,25-(OH)2D3, whilejejunal PXR expression was only stimulated in sheep supplemented with 25-OHD3. Either treatmentsincreased renal, but not ruminal, jejunal or hepatic expression of RXRa. These results demonstrate thatthe impact of large doses of vitamin D metabolites on different target organs and potential interactionswith other medications should be further investigated in vitro and in vivo to understand the effects ofvitamin D metabolites on metabolism and excretion pathways in livestock.