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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 hence only observed in normal extracellular Ca 2+ concentrations. However, the participation of Ca 2+ in the expression of the 24-hydroxylase gene in vivo is not known. The present studies investigate the role played by the circulating Ca 2+ and the D 3 and/or 1,25(OH) 2 D 3 status on the 1,25(OH) 2 D 3 -mediated inducibility of the 24-hydroxylase gene in rat duodenum. Hypocalcemic D-depleted rats were supplemented with calcium alone to normalize serum Ca 2+ without normalizing the D 3 status or 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 intestine of hypocalcemic D-depleted rats, and short- or long-term calcium supplementation was completely unsuccessful in inducing its expression. By contrast, acute 1,25(OH) 2 D 3 administration led to significant increases in the levels of expression of the gene which was independent of the calcium intake, the prevailing circulating Ca 2+ , and the D 3 or 1,25(OH) 2 D 3 status. Moreover, 24-hydroxylase gene expression was only found to respond to acutely administered 1,25(OH) 2 D 3 , the mRNA levels being unaltered following continuous exposure to physiological or pharmacological doses of the hormone for 7 days. Time-course studies revealed, however, that induction of the gene was clearly apparent early in the 1,25(OH) 2 D 3 supplementation course but gradually faded by 3 days to return to basal uninduced levels by 7 days, suggesting the presence of intestinal adaptation mechanism(s) which down-regulated the responsiveness in the continuous presence of 1,25 (OH) 2 D 3 . Our data show the lack of effect of calcium alone or in combination with 1,25(OH) 2 D 3 on the in vivo induction of the 24-hydroxylase gene expression 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 biotransformation pathway aimed at the irreversible clearance of the secosteroid hormone. (J Bone Miner Res 1995 ;10 :1148-1157)