Next, in the kidney, CYP27B1 hydroxylates 25(OH)D 3 at carbon 1 to generate 1,25(OH) 2D 3. First, vitamin D 3 is hydroxylated at carbon 25 by CYP2R1/CYP27A1 (cytochrome P450 enzymes) in the liver to generate 25-hydroxyvitamin D 3 (25(OH)D 3), a reliable serum marker for vitamin D status. The biologically active form of vitamin D 3, 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3), is generated by two hydroxylation steps. Since exposure to sunlight is a major trigger for vitamin D 3 synthesis in the skin, alterations in sunlight exposure based on season and latitude will influence the ability to synthesise vitamin D 3 ( Spiro & Buttriss 2014). Vitamin D 3 (cholecalciferol), a natural form of vitamin D, can be obtained from dietary sources (such as fatty fish) but is also generated in the human skin under influence of sunlight (UVB radiation, 290–320 nm) from its precursor, 7-dehydrocholesterol ( Leyssens et al. However, 1,25(OH) 2D 3 or its analogues seem biologically more active and may have more potential anticancer activity in BC upon combination with existing cancer therapies. However, most randomized controlled clinical trials do not demonstrate a clear decrease in BC incidence with vitamin D 3 supplementation. The presence of VDR in the majority of BCs, together with the various anti-tumoural effects of 1,25(OH) 2D 3, has supported the evaluation of the effects of vitamin D 3 supplementation on BC development. Recent insights also demonstrate that 1,25(OH) 2D 3 treatment impacts on cell metabolism and on the cancer stem cell population.
Nevertheless, multiple and in vivo preclinical studies illustrate that 1,25(OH) 2D 3 or its less calcaemic structural analogues influence diverse cellular processes in BC such as proliferation, differentiation, apoptosis, autophagy and the epithelial–mesenchymal transition. Mendelian randomization studies, however, did not find any relationship between single-nucleotide polymorphisms in genes associated with lower serum 25(OH)D and BC risk. Interestingly, several epidemiological studies show that low levels of 25(OH)D, a biological marker for 1,25(OH) 2D 3 status, are associated with an increased risk of breast cancer (BC) development. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH) 2D 3.
It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. The active form of vitamin D 3, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3), is primarily known as a key regulator of calcium and phosphate homeostasis.
0 kommentar(er)
