Ritter C S, Armbrecht H J, Slatopolsky E, Brown A J
Renal Division, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Kidney Int. 2006 Aug;70(4):654-9. doi: 10.1038/sj.ki.5000394.
Active vitamin D compounds repress parathyroid hormone (PTH) gene transcription and block chief cell hyperplasia, making them integral tools in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Recently, human parathyroid glands have been shown to express 25-hydroxyvitamin D 1alpha-hydroxylase (1alphaOHase), but documentation of the 1alphaOHase activity in parathyroid cells and its potential role in activating 25-hydroxyvitamin D(3) (25(OH)D(3)) to 1,25-dihydroxyvitamin D(3) (1,25(OH)2D3) have not been reported. The relative potencies of 25(OH)D(3) and 1,25(OH)(2)D(3) in reducing PTH secretion and mRNA were determined in primary cultures of bovine parathyroid cells (bPTC). The effects of blocking 1alphaOHase activity on suppression of PTH mRNA and induction of 24-hydroxylase mRNA were examined. Vitamin D receptor (VDR) affinities were estimated by intact cell competitive binding assay. Metabolism of 25(OH)D(3) by bPTC was assessed using a radioimmunoassay that measures all 1-hydroxylated metabolites of vitamin D. 25(OH)D(3) suppressed PTH secretion and mRNA (ED(50)=2 nM), but was several hundred times less potent than 1,25(OH)(2)D(3). The lower potency of 25(OH)D(3) correlated with its lower VDR affinity. bPTCs converted 25(OH)D(3) to 1-hydroxylated metabolites, but the rate of conversion was low. Inhibition of 1alphaOHase with the cytochrome P450 inhibitor clotrimazole did not block 25(OH)D(3)-mediated suppression of PTH. Clotrimazole enhanced 24-hydroxylase mRNA induction, presumably by inhibiting catabolism of 25(OH)D(3). In conclusion, 25(OH)D(3) suppresses PTH synthesis by parathyroid cells, possibly by direct activation of the VDR.
活性维生素D化合物可抑制甲状旁腺激素（PTH）基因转录并阻止主细胞增生，使其成为治疗慢性肾病患者继发性甲状旁腺功能亢进的重要工具。最近，已证明人类甲状旁腺表达25-羟维生素D 1α-羟化酶（1αOHase），但甲状旁腺细胞中1αOHase活性及其在将25-羟维生素D3（25(OH)D3）激活为1,25-二羟维生素D3（1,25(OH)2D3）中的潜在作用尚未见报道。在牛甲状旁腺细胞（bPTC）原代培养物中测定了25(OH)D3和1,25(OH)2D3在降低PTH分泌和mRNA方面的相对效力。研究了阻断1αOHase活性对抑制PTH mRNA和诱导24-羟化酶mRNA的影响。通过完整细胞竞争性结合试验估计维生素D受体（VDR）亲和力。使用测量维生素D所有1-羟化代谢物的放射免疫测定法评估bPTC对25(OH)D3的代谢。25(OH)D3抑制PTH分泌和mRNA（半数有效剂量=2 nM），但其效力比1,25(OH)2D3低数百倍。25(OH)D3较低的效力与其较低的VDR亲和力相关。bPTC将25(OH)D3转化为1-羟化代谢物，但转化率较低。用细胞色素P450抑制剂克霉唑抑制1αOHase并不阻断25(OH)D3介导的PTH抑制作用。克霉唑增强了24-羟化酶mRNA的诱导，可能是通过抑制25(OH)D3的分解代谢。总之，25(OH)D3可能通过直接激活VDR来抑制甲状旁腺细胞合成PTH。
