Slatopolsky E, Finch J, Ritter C, Takahashi F
Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA.
Am J Kidney Dis. 1998 Oct;32(2 Suppl 2):S40-7. doi: 10.1053/ajkd.1998.v32.pm9808142.
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.
维生素D的活性代谢产物骨化三醇[1,25(OH)₂D₃]可抑制甲状旁腺激素(PTH)基因转录及PTH分泌。尽管1,25(OH)₂D₃对抑制尿毒症患者的继发性甲状旁腺功能亢进有效，但由于高钙血症，在某些患者中强制使用大量钙盐来控制血清磷可能会妨碍使用理想治疗剂量的1,25(OH)₂D₃。我们研究了一种新的骨化三醇类似物，19-去甲-1,25(OH)₂D₂，其具有低血钙和低血磷活性。我们已明确证明，这种骨化三醇类似物可抑制尿毒症大鼠的继发性甲状旁腺功能亢进，而不会诱发高钙血症或高磷血症。此外，这种维生素D类似物以与1,25(OH)₂D₃相似的方式抑制前甲状旁腺素原信使核糖核酸。与1,25(OH)₂D₃增加肠道维生素D受体的作用相反，这种维生素D类似物会抑制肠道维生素D受体。这一发现可能对这些研究中所见的19-去甲-1,25(OH)₂D₂缺乏血钙活性至关重要。肠道维生素D受体缺乏增加的一个解释是，19-去甲-1,25(OH)₂D₂会降低内源性1,25(OH)₂D₃水平。总之，我们已表明，骨化三醇的新类似物19-去甲-1,25(OH)₂D₂对抑制继发性甲状旁腺功能亢进的尿毒症大鼠的PTH有效。此外，肠道中的维生素D受体显著减少，这可能部分解释了这种类似物较低的血钙和高磷效应。
