1,25-Dihydroxyvitamin D-3 downregulates the rat intestinal vitamin D-3-25-hydroxylase CYP27A

The vitamin D-3-25-hydroxylase CYP27A is located predominantly in liver, bu t its expression is also detected in extrahepatic tissues. Our aim was to e valuate the regulation of CYP27A by vitamin D-3 (D-3) or its metabolites in rat duodena. Vitamin D-depleted rats were repleted with D-3, 25-hydroxyvit amin D (25OHD), or 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] or acutely in jected 1,25(OH)(2)D-3 to investigate the mechanisms of action of the hormon e. All D-3 compounds led to a progressive decrease in CYP27A mRNA, with lev els after D-3 representing 20% of that observed in D depletion. 25OHD decre ased CYP27A mRNA by 55%, whereas 1,25(OH)(2)D-3 led to a 40% decrease, whic h was accompanied by a 31% decrease in CYP27A protein levels and an 89% dec rease in enzyme activity. Peak circulating 1,25(OH)(2)D-3 concentrations we re, however, the highest in D-3-repleted, followed by 25OHD- and 1,25(OH)(2 )D-3-repleted animals. 1,25(OH)(2)D-3 resulted in a decrease in both CYP27A mRNA half-life and transcription rate. Our data illustrate that the intest ine expresses the D-3-25-hydroxylase and that the gene is highly regulated in vivo through a direct action of 1,25(OH)(2)D-3 or through the local prod uction of D-3 metabolites.