Attenuated up-regulation of vitamin D-dependent calcium-binding proteins by 22-oxa-1,25-dihydroxyvitamin D3 in uremic rats: A possible mechanism for less-calcemic action

SUMMARY: 22-Oxa-1,25-dihydroxyvitamin D₃ (OCT) is an analogue of vitamin D with less calcemic action than 1,25-dihydroxyvitamin D₃ (1,25D3), and thus may be advantageous in the treatment of secondary hyperparathyroidism in dialysis patients. to further elucidate the mechanisms of less-calcemic action of OCT in chronic renal failure, we examined the effects of OCT and 1,25D3 on mRNA levels for vitamin D-dependent 9-KDa calcium binding protein (CaBP-D_9K) in the intestinal mucosa and 28-KDa (CaBP-D_28K) in the kidney. In Sprague-Dawley rats made uremic by 5/6 nephrectomy for three months, OCT at doses of 0.25, 1.25 and 6.25 μg/kg, or 1,25D3 at 0.025,0.125 and 0.625 μg/kg were administered intravenously three times per week for two weeks. At 24 h after the final injection, enhanced serum PTH and PTH mRNA levels were successfully suppressed both by OCT and 1,25D3 in a dose dependent manner. However, OCT induced less hypercalcemia than 1,25D3. 1,25D3 markedly upregulated the expression of CaBP-D_9K and CaBP-D_28K genes, while they were not affected by OCT at all. In conclusion, such attenuated effects of OCT on calcium-binding proteins may play a role in the noncalcemic action, because number of CaBP-D_9K has been suggested to correlate with calcium absorption in the intestine.     

In vitro suppression of parathyroid hormone secretion by 22-oxa-calcitriol in human parathyroid hyperplasia due to uraermia

SUMMARY: 22-oxa-calcitriol (OCT), a vitamin D analogue, suppresses parathyroid hormone (PTH) secretion and has less calcaemic activity than 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] in vivo. In this study, we evaluated the effect of OCT on PTH secretion in vitro using human hyperplastic parathyroid tissue obtained during surgery for advanced renal hyperparathyroidism and normal bovine parathyroid glands to compare the effects of 1,25(OH)₂D₃. 22-oxa-calcitriol suppressed PTH secretion by nodular hyperplastic parathyroid tissue and normal bovine tissue in a dose dependent manner, the same as 1,25(OH)₂D₃. We showed the additive effect of extracellular calcium level on suppression of PTH secretion by OCT and 1,25(OH)₂D₃. These results suggest that OCT suppresses PTH secretion, the same as 1,25(OH)₂D₃ not only in normal parathyroid cells but also on hyperplastic parathyroid cells.