INDUCTION OF VITAMIN-D 24-HYDROXYLASE MESSENGER-RNA AND ACTIVITY BY 22-OXACALCITRIOL IN MOUSE KIDNEY AND DUODENUM - POSSIBLE ROLE IN DECREASE OF PLASMA 1-ALPHA,25-DIHYDROXYVITAMIN-D-3

The synthetic analog of 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], 22-oxacalcitriol (OCT), retains most of the properties of 1,25(OH)(2)D-3 but exhibits much less hypercalcemic action than the parent compound. The effects of OCT on plasma calcium, phosphorus, and 1 alpha,25-dihydroxyvitamin D [1,25(OH)(2)D] concentrations were examined in mice. Administration of a single dose (24 pmol/g body wt, i.p.) of OCT had no effect on plasma calcium for up to 48 hr, significantly increased plasma phosphorus at 4 and 8 hr and significantly reduced the concentration of 1,25(OH)(2)D in plasma between 4 and 48 hr. Both OCT and 1,25(OH)(2)D-3 at 24 pmol/g body wt (i.p.) induced a single, 3.4-kb mRNA encoding vitamin D 24-hydroxylase (24-OHase), the cytochrome P450 enzyme responsible for 1,25(OH)(2)D-3 degradation, in kidney and duodenum. The OCT-induced increase in 24-OHase mRNA and an increase in enzyme activity were marked at 2 and 4 hr in both tissues. In kidney, mRNA abundance had decreased by 8 hr but remained above basal values far up to 30 hr; activity remained relatively high for up to 48 hr. In duodenum, 24-OHase mRNA abundance returned virtually to control values by 8 hr after OCT treatment; activity remained at nearly maximal levels for up to 30 hr but was decreased at 48 hr. The effects of OCT and 1,25(OH)(2)D-3 on 24-OHase mRNA abundance and enzyme activity were dose-dependent in kidney and duodenum. Whereas the dose-response relations for the effects of both compounds on 24-OHase mRNA were similar, OCT was slightly more potent than 1,25(OH)(2)D-3 in stimulating 24-OHase activity in both tissues. These results suggest that the OCT-induced decrease in plasma 1,25(OH)(2)D-3 is attributable, at least in part, to an increased degradation of 1,25(OH)(2)D-3 which results from an increase in 24-OHase abundance and enzyme activity.