Nonhypercalcemic vitamin D analogs: interactions with the vitamin D-binding protein.
The natural vitamin D hormone, 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3), not only regulates serum and bone calcium homeostasis but is probably also a paracrine factor in several cells and tissues including skin, immune system, placenta and brain, where it stimulates cell differentiation and inhibits cell proliferation. Several structural analogs of 1 alpha, 25-(OH)2D3 not only have superagonist activity but also display a selective action profile: indeed they maintain or have increased activity on cell differentiation/proliferation but also have substantially decreased calcemic activity when compared to 1 alpha,25-(OH)2D3. This decreased calcemic activity is partially due to mere pharmacological reasons: because of low binding affinity for the plasma vitamin D-binding protein, a more rapid extracellular metabolism and increased cellular uptake is possible when compared to 1 alpha,25-(OH)2D3. Their short extracellular half-life combined with comparable or enhanced transactivation potency together with analog-and cell-type-specific intracellular metabolism can probably explain why some analogs have a unique combination of superagonist activity and specific action profile with favorable dissociation of differentiation versus calcemic potency.
Bouillon
R
R
Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Onderwijs en Navorsing, Gasthuisberg, Leuven, België.
Verstuyf
A
A
Zhao
J
J
Tan
B K
BK
Van Baelen
H
H
D000818:Animals; D002118:Calcium / Q000097:blood*; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives*; D014809:Vitamin D-Binding Protein / Q000378:metabolism*
D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; D002118:Calcium