Comparative effects of 1α‐hydroxyvitamin D 3 and 1,25‐dihydroxyvitamin D 3 on transporters and enzymes in fxr(+/+) and fxr(‐/‐) mice

Previous studies have shown that 1α,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P‐gp expression. The present study compared the equimolar efficacies of 1α‐hydroxyvitamin D 3 [1α(OH)D 3 ] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half‐life that is converted to 1,25(OH) 2 D 3 , and 1,25(OH) 2 D 3 on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)‐directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [ fxr (+/+)] and FXR knockout [ fxr (‐/‐)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D 3 and 1,25(OH) 2 D 3 , 1α(OH)D 3 treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr (+/+) and fxr (‐/‐) mice compared to 1,25(OH) 2 D 3 treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P‐gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D 3 treatment. The higher activity of 1α(OH)D 3 was explained by its rapid conversion to 1,25(OH) 2 D 3 in tissue sites, furnishing higher plasma and tissue 1,25(OH) 2 D 3 levels compared to following 1,25(OH) 2 D 3 ‐treatment. In conclusion, 1α(OH)D 3 exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH) 2 D 3 in mice. Copyright © 2013 John Wiley & Sons, Ltd.