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

In order to improve calcium and phosphorus balance, beef cattle and dairy cows can be supplemented with vitamin D. However, different vitamin D metabolites have been shown to increase expression of P-glycoprotein (P-gp, MDR1, ABCB1) and cytochrome P450 3A (CYP3A) in rodents as well as in cell culture systems. As such interferences might have an impact on pharmacokinetics of some drugs widely-used in veterinary medicine, we investigated the expression of P-gp, CYP3A, vitamin D receptor (VDR), pregnane X receptor (PXR) and retinoid X receptor α (RXRα) in sheep either treated orally with 6μg/kg body weight (BW) 25-hydroxyvitamin D3 (OHD3) for ten days before sacrifice or 12h after intravenous injection of 0.5μg/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, this effect 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 no impact. Renal expression of VDR and PXR was also increased by treatment with 1,25-(OH)2D3, while jejunal PXR expression was only stimulated in sheep supplemented with 25-OHD3. Either treatments increased renal, but not ruminal, jejunal or hepatic expression of RXRα. These results demonstrate that the impact of large doses of vitamin D metabolites on different target organs and potential interactions with other medications should be further investigated in vitro and in vivo to understand the effects of vitamin D metabolites on metabolism and excretion pathways in livestock.