A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content.
A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content.
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1,25-(OH)2D3 的新类似物 19-NOR-1,25-(OH)2D2 可抑制尿毒症大鼠的血清 PTH 和甲状旁腺生长，而不升高肠道维生素 D 受体含量。
DOI：
10.1016/s0272-6386(97)90571-0
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发表时间：
1997
期刊：
影响因子：
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通讯作者：
Slatopolsky,E
中科院分区：
文献类型：
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作者：
Takahashi,F;Finch,JL;Denda,M;Dusso,AS;Brown,AJ;Slatopolsky,E
我们以前曾报道，19-去甲-1，25-（OH）_2D_2，一种新的1，25-（OH）_2D_3类似物，在无高钙血症或高磷血症的情况下抑制尿毒症大鼠的甲状旁腺激素（PTH）分泌。在本研究中，我们研究了19-去甲-1，25-（OH）_2D_2对甲状旁腺生长和肠道维生素D受体（VDR）含量的影响。通过5/6肾切除诱导尿毒症后，将大鼠分为5个实验组，每周三次腹腔注射溶媒、1，25-（OH）2D 3（2或6 ng/大鼠）或19-去甲-1，25-（OH）2D 2（25或100 ng/大鼠），持续8周。12只正常大鼠接受溶剂，作为正常对照组。在研究过程中，大鼠维持1.0%钙和0.8%磷的饮食。高剂量1，25-（OH）_2D_3（6 ng）使PTH从尿毒症对照组的52.7 ± 10.2pg/mL降至25.7 ± 6.7pg/mL（P < 0.01）。然而，该剂量的1，25-（OH）2D 3增加了离子钙（4.71 ± 0.05至4.85 ± 0.06 mg/dL; P < 0.05）和磷（4.34 ± 0.30至6.67 ± 0.63 mg/dL; P < 0.01）的血清水平。19-去甲-1，25-（OH）_2D_2和1，25-（OH）_2D_3均能有效降低血清PTH，而不改变血清钙和磷。100 ng剂量的19-去甲-1，25-（OH）_2D_2使PTH降至20.7 ± 3.1pg/mL（P < 0.01），抑制甲状旁腺生长50%以上。19-去甲-1，25-（OH）_2D_2两种剂量均能降低尿毒症大鼠内源性1，25-（OH）_2D_3水平（25 ng：30.4 ± 2.0，P < 0.05; 100 ng：27.9 ± 3.2，P < 0.01，v 48.4 ± 6.6 pg/mL）。与接受两种剂量的19-去甲-1，25-（OH）2D 2的动物相比，6-ng剂量的1，25-（OH）2D 3增加了肠道VDR含量（138.5 ± 20.0 fmol/mg蛋白）（25 ng：84.0 ± 11.9，P < 0.05; 100 ng：78.4 ± 10.9，P < 0.01）。这可能是由于两种剂量的19-nor-1，25-（OH）2D 2均导致内源性1，25-（OH）2D 3水平显著降低，因为肠VDR与血清1，25-（OH）2D 3直接相关（r = 0.963; P = 0.008）。因此，与肠道相比，19-去甲-1，25-（OH）2D 2似乎对甲状旁腺产生选择性作用。其低钙和低磷特性可能是由于内源性1，25-（OH）2D 3水平降低导致肠道VDR减少。这种选择性使这种类似物成为治疗继发性甲状旁腺功能亢进的理想药物。
We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3(2 or 6 ng/rat), or 19-nor-1,25-(OH)2D2(25 or 100 ng/ rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 ± 10.2 pg/mL in the uremic control group to 25.7 ± 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 ± 0.05 to 4.85 ± 0.06 mg/dL; P < 0.05) and phosphorus (4.34 ± 0.30 to 6.67 ± 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2decreased serum PTH as effectively as 1,25-(OH)2D3without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor-1,25-(OH)2D2decreased PTH to 20.7 ± 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25-(OH)2D2also decreased endogenous 1,25-(OH)2D3levels compared with uremic control rats (25 ng: 30.4 ± 2.0, P < 0.05, and 100 ng: 27.9 ± 3.2, P < 0.01, v 48.4 ± 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3elevated intestinal VDR content (138.5 ± 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2(25 ng: 84.0 ± 11.9, P < 0.05, and 100 ng: 78.4 ± 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25-(OH)2D3levels caused by both doses of 19-nor-1,25-(OH)2D2because intestinal VDR correlated directly with serum 1,25-(OH)2D3(r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.