NONHYPERCALCEMIC VITAMIN-D ANALOGS - INTERACTIONS WITH THE VITAMIN-D-BINDING PROTEIN

The natural vitamin D hormone, 1 alpha,25-dihydroxyvitamin D-3 (1 alph a,25-(OH)(2)D-3), not only regulates serum and bone calcium homeostasi s but is probably also a paracrine factor in several cells and tissues including skin, immune system, placenta and brain, where it stimulate s cell differentiation and inhibits cell proliferation. Several struct ural analogs of 1 alpha,25-(OH)(2)D-3 not only have superagonist activ ity but also display a selective action profile: indeed they maintain or have increased activity on cell differentiation/proliferation but a lso have substantially decreased calcemic activity when compared to 1 alpha,25-(OH)(2)D-3. 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 metab olism and increased cellular uptake is possible when compared to 1 alp ha,25-(OH)(2)D-3. Their short extracellular half-life combined with co mparable 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 sp ecific action profile with favorable dissociation of differentiation v ersus calcemic potency.