PDF(Pubmed)
Abstract：
Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys. Interestingly, a recently identified mutation in another CYP enzyme, CYP3A4 (gain-of-function), caused type III vitamin D-dependent rickets. CYP3A are also expressed in the intestine, but their hydroxylation activities towards vitamin D substrates are unknown. We evaluated CYP3A or CYP24A1 activities on vitamin D action in cultured cells. In addition, we examined the expression level and regulation of CYP enzymes in intestines from mice. The expression of CYP3A or CYP24A1 significantly reduced 1,25(OH)2D3-VDRE activity. Moreover, in mice, Cyp24a1 mRNA was significantly induced by 1,25(OH)2D3 in the intestine, but a mature form (approximately 55 kDa protein) was also expressed in mitochondria and induced by 1,25(OH)2D3, and this mitochondrial enzyme appears to hydroxylate 25OHD3 to 24,25(OH)2D3. Thus, CYP3A or CYP24A1 could locally attenuate 25OHD3 or 1,25(OH)2D3 action, and we suggest the small intestine is both a vitamin D target tissue, as well as a newly recognized vitamin D-metabolizing tissue.
摘要：
肝脏/肾脏中的维生素D羟基化导致转化为其生理活性形式的1,25-二羟基维生素D3[1,25(OH)2D3]。1,25(OH)2D3通过主要在肠上皮细胞中表达的核维生素D受体(VDR)控制基因表达。细胞色素P450(CYP)24A1是在肾脏中表达的分解代谢酶。有趣的是,最近发现的另一种CYP酶的突变，CYP3A4（功能增益），引起的III型维生素D依赖性病。CYP3A也在肠道中表达，但它们对维生素D底物的羟基化活性尚不清楚。我们评估了CYP3A或CYP24A1对培养细胞中维生素D作用的活性。此外,我们检测了CYP酶在小鼠肠道中的表达水平和调节。CYP3A或CYP24A1的表达显著降低1,25(OH)2D3-VDRE活性。此外，在老鼠身上，1,25（OH）2D3在肠道中显著诱导Cyp24a1mRNA，但是在线粒体中也表达了成熟形式（约55kDa蛋白质），并由1,25（OH）2D3诱导，并且该线粒体酶似乎将25OHD3羟基化为24,25（OH）2D3。因此，CYP3A或CYP24A1可以局部减弱25OHD3或1,25(OH)2D3的作用，我们认为小肠既是维生素D的靶组织，以及新发现的维生素D代谢组织。
