Avila Euclides, Díaz Lorenza, Barrera David, Halhali Ali, Méndez Isabel, González Leticia, Zuegel Ulrich, Steinmeyer Andreas, Larrea Fernando
Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000, México D.F., Mexico.
J Steroid Biochem Mol Biol. 2007 Jan;103(1):90-6. doi: 10.1016/j.jsbmb.2006.07.010. Epub 2006 Oct 31.
Human placenta synthesizes and metabolizes 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)/calcitriol] through the activity of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (CYP27B1) and 1,25(OH)(2)D(3)-24-hydroxylase (CYP24A1), the two key enzymes for Vitamin D metabolism. In this study, calcitriol rapidly generated intracellular cAMP accumulation in cultured human syncytiotrophoblast cells, which in turn enhanced hCG secretion, a marker of trophoblast endocrine activity. The effects of 1,25(OH)(2)D(3) upon the expression of CYP27B1 and CYP24A1 were also investigated. 1,25(OH)(2)D(3) and activators of the PKA signaling system decreased the expression of CYP27B1, whereas increased CYP24A1 gene transcription. The use of a selective inhibitor of PKA (H-89) prevented the effects of calcitriol on CYP27B1 gene and hCG secretion, but not on CYP24A1 transcription. Addition of ZK 159222, a Vitamin D receptor (VDR) antagonist, blocked the calcitriol-mediated upregulation of 24-hydroxylase gene expression but did not affect calcitriol-induced downregulation of CYP27B1 gene or hCG stimulation. In addition, our study also demonstrated a role of calcitonin on Vitamin D hydroxylases gene regulation in placenta. The overall data suggest that calcitriol downregulates CYP27B1 expression via a cAMP-dependent signaling pathway, whereas upregulates 24-hydroxylase gene expression through a VDR-dependent mechanism.
人胎盘通过25-羟基维生素D3-1α-羟化酶（CYP27B1）和1,25（OH）2D3-24-羟化酶（CYP24A1）的活性来合成和代谢1,25-二羟基维生素D（3）[1,25（OH）2D（3）/骨化三醇]，这两种酶是维生素D代谢的关键酶。在本研究中，骨化三醇在培养的人合体滋养层细胞中迅速产生细胞内cAMP积累，进而增强hCG分泌，hCG是滋养层内分泌活性的标志物。还研究了1,25（OH）2D（3）对CYP27B1和CYP24A1表达的影响。1,25（OH）2D（3）和PKA信号系统激活剂降低了CYP27B1的表达，而增加了CYP24A1基因转录。使用PKA的选择性抑制剂（H-89）可阻止骨化三醇对CYP27B1基因和hCG分泌的影响，但不影响CYP24A1转录。添加维生素D受体（VDR）拮抗剂ZK 159222可阻断骨化三醇介导的24-羟化酶基因表达上调，但不影响骨化三醇诱导的CYP27B1基因下调或hCG刺激。此外，我们的研究还证明了降钙素在胎盘维生素D羟化酶基因调控中的作用。总体数据表明，骨化三醇通过cAMP依赖性信号通路下调CYP27B1表达，而通过VDR依赖性机制上调24-羟化酶基因表达。
