Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA.
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):13-9. doi: 10.1016/j.jsbmb.2010.03.065. Epub 2010 Mar 27.
The cytochrome P450 enzyme 24-hydroxylase (CYP24) plays a critical role in regulating levels of vitamin D hormone. Aberrant expression of CYP24 has been implicated in vitamin D insufficiency and resistance to vitamin D therapy. We have demonstrated amplified CYP24 expression in uremic rats, suggesting that CYP24 has an etiological role in vitamin D insufficiency commonly associated with chronic kidney disease (CKD). We have designed two new analogues of 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), namely CTA091 and CTA018/MT2832, which are potent inhibitors of CYP24. In vitro studies with CTA091 show that it enhances the potency of 1alpha,25(OH)2D3. In vivo studies demonstrate that CTA091 decreases serum intact parathyroid hormone (iPTH) levels and increases circulating 1alpha,25(OH)2D3. CTA091 increases both Cmax and AUC of co-administered 1alpha,25(OH)2D3. These studies indicate that CYP24 inhibition can increase cellular responsiveness to vitamin D hormone and potentiate vitamin D therapy. CTA018/MT2832 differs from CTA091 in that it also has the ability to activate vitamin D receptor-mediated transcription. CTA018/MT2832 effectively suppresses elevated iPTH secretion at doses which do not affect serum calcium or phosphorus levels in a rodent model of CKD. Studies with both new analogues underscore the potential utility of CYP24 inhibition in the treatment of secondary hyperparathyroidism in CKD.
细胞色素 P450 酶 24-羟化酶（CYP24）在调节维生素 D 激素水平方面起着关键作用。CYP24 的异常表达与维生素 D 不足和对维生素 D 治疗的抵抗有关。我们已经证明尿毒症大鼠中 CYP24 的表达增加，这表明 CYP24 在维生素 D 不足中具有病因作用，这种不足通常与慢性肾脏病（CKD）有关。我们设计了两种 1α，25-二羟维生素 D3（1α，25（OH）2D3）的新类似物，即 CTA091 和 CTA018/MT2832，它们是 CYP24 的有效抑制剂。CTA091 的体外研究表明，它增强了 1α，25（OH）2D3 的效力。体内研究表明，CTA091 降低血清完整甲状旁腺激素（iPTH）水平并增加循环 1α，25（OH）2D3。CTA091 增加了同时给予的 1α，25（OH）2D3 的 Cmax 和 AUC。这些研究表明，CYP24 抑制可以增加细胞对维生素 D 激素的反应性并增强维生素 D 治疗。CTA018/MT2832 与 CTA091 的不同之处在于它还具有激活维生素 D 受体介导的转录的能力。CTA018/MT2832 以不影响血清钙或磷水平的剂量有效抑制 CKD 啮齿动物模型中升高的 iPTH 分泌。这两种新类似物的研究强调了 CYP24 抑制在 CKD 继发性甲状旁腺功能亢进症治疗中的潜在应用。
