2007) that reduces epigenetic DNA methylation. 2010), which may be enhanced through synergistic action with a demethylating drug (Koschmieder et al. However, both calcidiol and calcitriol are active hormones and cofactors in hematopoiesis, thus explaining observations indicating a differentiating effect of VD on hematopoietic and leukemic cells (Collins 1987 Sim et al. This would determine the biological output of VD action (Tuohimaa 2009) and has the potential to reflect the clinical situation better than calcitriol. Calcidiol uptake is mediated by megalin-mediated endocytosis of the VD binding protein calcidiol complex. 2009).Īlthough previously termed as an inactive prohormone, it has been found that both calcidiol and calcitriol are active hormones and act together. As early as 1986, it was postulated that calcitriol (the active form of VD) and a variety of VD analogs affect proliferation and differentiation of normal and leukemic cells of the myeloid line (Munker et al. Several animal models of cancer have demonstrated the essential role of VD as a chemopreventive agent, mainly because it induces cell cycle arrest and influences cellular differentiation (Dace et al. VD may be termed as a hormone because endogenous production of its essential precursor is UVB-stimulated photoconversion of 7-dehydrocholesterol in skin, in addition to a few dietary sources (Lin and White 2004), followed by processing via liver and kidney (Fig.
#METABOLIC SYNERGY VITAMINS SERIES#
Interest in the role of epigenetics in VD metabolism is nourished by the fact that it influences many metabolic factors promoting a series of epigenetic mechanisms which are dysregulated in the etiology of numerous diseases. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elucidate complex epigenetic mechanisms for cancer preventive actions of VD.Īpart from its original definition as a regulator of calcium homeostasis, vitamin D (VD) is now known to have a broad spectrum of actions as illustrated by a large number of diseases resulting from an insufficient VD supply or VD metabolism (Fig. HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs).
Activity of VDR can be modulated epigenetically by histone acetylation. Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). The bioactive vitamin D (VD) metabolite, 1,25-dihydroxyvitamin D 3 regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR).
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