25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand

J Steroid Biochem Mol Biol. 2010 Feb 15;118(3):162-70. doi: 10.1016/j.jsbmb.2009.11.011. Epub 2009 Nov 26.

Abstract

25-Hydroxyvitamin D(3) 1alpha-hydroxylase encoded by CYP27B1 converts 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3), a vitamin D receptor ligand. 25-Hydroxyvitamin D(3) has been regarded as a prohormone. Using Cyp27b1 knockout cells and a 1alpha-hydroxylase-specific inhibitor we provide in four cellular systems, primary mouse kidney, skin, prostate cells and human MCF-7 breast cancer cells, evidence that 25-hydroxyvitamin D(3) has direct gene regulatory properties. The high expression of megalin, involved in 25-hydroxyvitamin D(3) internalisation, in Cyp27b1(-/-) cells explains their higher sensitivity to 25-hydroxyvitamin D(3). 25-Hydroxyvitamin D(3) action depends on the vitamin D receptor signalling supported by the unresponsiveness of the vitamin D receptor knockout cells. Molecular dynamics simulations show the identical binding mode for both 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) with the larger volume of the ligand-binding pocket for 25-hydroxyvitamin D(3). Furthermore, we demonstrate direct anti-proliferative effects of 25-hydroxyvitamin D(3) in human LNCaP prostate cancer cells. The synergistic effect of 25-hydroxyvitamin D(3) with 1alpha,25-dihydroxyvitamin D(3) in Cyp27b1(-/-) cells further demonstrates the agonistic action of 25-hydroxyvitamin D(3) and suggests that a synergism between 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) might be physiologically important. In conclusion, 25-hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand with gene regulatory and anti-proliferative properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 24,25-Dihydroxyvitamin D 3 / pharmacology
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / antagonists & inhibitors
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • Animals
  • Binding Sites
  • Calcifediol / chemistry
  • Calcifediol / metabolism*
  • Calcifediol / pharmacology
  • Calcitriol / chemistry
  • Calcitriol / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Kidney / cytology
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Dynamics Simulation
  • Prostate / cytology
  • Protein Structure, Tertiary
  • Receptors, Calcitriol / agonists*
  • Receptors, Calcitriol / chemistry
  • Receptors, Calcitriol / genetics
  • Skin / cytology
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Vitamin D3 24-Hydroxylase

Substances

  • Enzyme Inhibitors
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
  • Receptors, Calcitriol
  • 24,25-Dihydroxyvitamin D 3
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Calcitriol
  • Calcifediol