IN-VIVO REGULATION OF RAT INTESTINAL 24-HYDROXYLASE - POTENTIAL NEW ROLE OF CALCITONIN

24-Hydroxylase is found in many mammalian tissues and is required as a n initial step in the deactivation of vitamin D-3 metabolites and most of its active analogs. We studied the regulation of intestinal 24-hyd roxylase (I-24-OHase) activity and messenger RNA (mRNA) expression in rats as influenced by calcium and vitamin D status. Rats were fed vita min D-replete diets containing either normal calcium (1.0-1.2%, design ated NC) or low calcium (0.02%; designated LC). Half of the NC and LC rats received 25,000 IU vitamin D-3 three times weekly, orally, and we re designated NCT and LCT, respectively. We found that I-24-OHase mRNA expression was up-regulated in rats receiving excess vitamin Ds (NCT and LCT). We observed, however, that the up-regulation was much more d ramatic in the LCT group and exceeded by 4.5-fold that observed in the NCT group. Plasma calcium was also elevated in the NCT group (12.6 +/ - 0.2 mg/dl), but not the LCT group (10.5 +/- 0.15 mg/dl). We, therefo re, examined the possibility that calcitonin released in response to h ypercalcemia may have suppressed the induced expression of I-24-OHase mRNA in the NCT group. The plasma calcitonin level was higher in the N CT group (36.14 +/- 2.46 pg/ml) relative to that in the LCT group (19. 38 +/- 2.28 pg/ml). Thyroparathyroidectomy also resulted in a 2-fold ( P < 0.001) increase in I-24-OHase activity in the NCT group, a respons e that was reversed (within 4 h) with a single dose of calcitonin (100 IU/rat). Calcitonin administration to LCT rats also resulted in a sig nificant (P < 0.001) 5-fold reduction in I-24-OHase mRNA expression. T hese data suggest that calcitonin is a potent negative regulator of I- 24-OHase mRNA expression and I-24-OHase activity and that the release of calcitonin may block an important pathway for the inactivation of v itamin D-3 metabolites in intestine and, thereby, potentiate the toxic ity of vitamin D-3 during periods of its excess consumption.