Effects of 19-nor-1,25(OH)2D2, a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats.
The active metabolite of vitamin D, calcitriol [1,25(OH)2D3] suppresses parathyroid hormone (PTH) gene transcription and PTH secretion. Although 1,25(OH)2D3 is effective in suppressing secondary hyperparathyroidism in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude in some patients the use of ideal therapeutic doses of 1,25(OH)2D3 because of hypercalcemia. We have studied a new analogue of calcitriol,19-nor-1,25(OH)2D2 that possesses low calcemic and phosphatemic activity. We have clearly demonstrated that this analogue of calcitriol can suppress secondary hyperparathyroidism without inducing hypercalcemia or hyperphosphatemia in uremic rats. In addition, this analogue of vitamin D supresses pre-pro PTH messenger RNA in a similar fashion to that of 1,25(OH)2D3. Contrary to the effect of 1,25(OH)2D3 that increases the intestinal vitamin D receptor, this analogue of vitamin D suppresses the intestinal vitamin D receptor. This finding may be critical for the lack of calcemic activity of 19-nor-1,25(OH)2D2 seen in these studies. One of the explanations for the lack of an increasing intestinal VDR is the fact that 19-nor-1,25(OH)2D2 decreases endogenous levels of 1,25(OH)2D3. In summary, we have shown that 19-nor-1,25(OH)2D2, a new analogue of calcitriol is effective in suppressing PTH in uremic rats with secondary hyperparathyroidism. In addition, there is a significant decrease in the VDR in the intestine, which may explain in part the less calcemic and hyperphosphatemic effect of this analogue.
Slatopolsky
E
E
Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA. eslatopo@imgate.wustl.edu
Finch
J
J
Ritter
C
C
Takahashi
F
F
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D007421:Intestine, Small / Q000378:metabolism; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism; D010758:Phosphorus / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism; D014511:Uremia / Q000150:complications*
D004872:Ergocalciferols; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D010758:Phosphorus; C084656:paricalcitol; D002117:Calcitriol; D002118:Calcium