Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia
Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia
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DOI：
10.1194/jlr.m700293-jlr200
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发表时间：
2008-04-01
影响因子：
6.5
通讯作者：
Makishima, Makoto
中科院分区：
文献类型：
--
作者：
Ishizawa, Michiyasu;Matsunawa, Manabu;Makishima, Makoto
1 α，25-二羟基维生素D-3 [1,25(OH)(2)D-3]是一种维生素D受体（VDR）配体，调节钙稳态，并在免疫和细胞分化中表现出非钙化作用。除了骨和钙代谢紊乱外，VDR配体在治疗免疫紊乱、微生物感染和恶性肿瘤方面也是潜在的治疗剂。高钙血症，维生素D-3衍生物的主要不良反应；限制了它们的临床应用。次生胆汁酸石胆酸（LCA）是VDR的另一种生理配体，其合成衍生物醋酸LCA是一种有效的VDR激动剂。在这项研究中，我们发现一个额外的衍生物，丙酸LCA，是一个比醋酸LCA更有选择性的VDR活化剂。乙酸LCA和丙酸LCA诱导肠细胞钙通道瞬时受体电位-香草酸6 （TRPV6）的表达与1 α，25-二羟基维生素D-3 24-羟化酶（CYP24A1）的表达一样有效，而1,25(OH)(2)D-3对TRPV6的表达比对CYP24A1的表达更有效。体内实验表明，乙酸LCA和丙酸LCA能有效诱导组织VDR激活，且不引起高钙血症。这些胆汁酸衍生物具有选择性VDR调节剂的功能。
1 alpha,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and also exhibits noncalcemic actions on immunity and cell differentiation. In addition to disorders of bone and calcium metabolism, VDR ligands are potential therapeutic agents in the treatment of immune disorders, microbial infections, and malignancies. Hypercalcemia, the major adverse effect of vitamin D-3 derivatives; limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR, and its synthetic derivative, LCA acetate, is a potent VDR agonist. In this study, we found that an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. LCA acetate and LCA propionate induced the expression of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) as effectively as that of 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase (CYP24A1), whereas 1,25(OH)(2)D-3 was more effective on TRPV6 than on CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate and LCA propionate effectively induced tissue VDR activation without causing hypercalcemia. These bile acid derivatives have the ability to function as selective VDR modulators.