EXPRESSION OF THE 1,25-DIHYDROXYVITAMIN D-3-24-HYDROXYLASE GENE IN RAT INTESTINE - RESPONSE TO CALCIUM, VITAMIN-D-3 AND CALCITRIOL ADMINISTRATION IN-VIVO

The 25(OH)D-3/1,25(OH)(2)D-3 24-hydroxylase (24-hydroxylase) displays an induction profile responsive to vitamin D (D) abundance and is henc e only observed in normal extracellular Ca2+ concentrations. However, the participation of Ca2+ in the expression of the 24-hydroxylase gene in vivo is not known. The present studies investigate the role played by the circulating Ca2+ and the D-3 and/or 1,25(OH)(2)D-3 status on t he 1,25(OH)(2)D-3-mediated inducibility of the 24-hydroxylase gene in rat duodenum, Hypocalcemic D-depleted rats were supplemented with calc ium alone to normalize serum Ca2+ without normalizing the D-3 status o r were acutely or chronically supplemented with D-3 or 1,25(OH)(2)D-3. Messenger RNA for the 24-hydroxylase was undetectable in the intestin e of hypocalcemic D-depleted rats, and short- or long-term calcium sup plementation was completely unsuccessful in inducing its expression, B y contrast, acute 1,25(OH)(2)D-3 administration led to significant inc reases in the levels of expression of the gene which was independent o f the calcium intake, the prevailing circulating Ca2+, and the D-3 or 1,25(OH)(2)D-3 status, Moreover, 24-hydroxylase gene expression was on ly found to respond to acutely administered 1,25(OH)(2)D-3, the mRNA l evels being unaltered following continuous exposure to physiological o r pharmacological doses of the hormone for 7 days, Time-course studies revealed, however, that induction of the gene,vas clearly apparent ea rly in the 1,25(OH)(2)D-3 supplementation course but gradually faded b y 3 days to return to basal uninduced levels by 7 days, suggesting the presence of intestinal adaptation mechanism(s) which down-regulated t he responsiveness in the continuous presence of 1,25(OH)(2)D-3. Our da ta show the lack of effect of calcium alone or in combination with 1,2 5(OH)(2)D-3 on the in vivo induction of the 24-hydroxylase gene expres sion in rat intestine. By rapidly reacting to surges in 1,25(OH)(2)D-3 concentrations, the 24-hydroxylase efficiently controls the amount of 1,25(OH)(2)D-3 in intestine as the first step in the biotransformatio n pathway aimed at the irreversible clearance of the secosteroid hormo ne.