Structure-function studies of the interaction of the hormonally active form of vitamin D 3, 1α,25-dihydroxy-vitamin D 3, with the intestine

Abstract

The steroid cholecalciferol or vitamin D 3 is known to undergo a successive two-step hydroxylation, first in the liver to give 25-OH-D 3 and then in the kidney to produce 1α,25-(OH) 2-D 3. The kidney is postulated to be the endocrine gland which produces the biologically active form of vitamin D. The biological response to 1α,25-(OH) 2-D 3 in the target intestine is believed to occur as a consequence of association with cytoplasmic and nuclear receptors, as is the case for other classical steroid hormones. A steroid competition assay has been devised using receptors present in the intestinal chromatin. A comparison of the relative competition in the assay and biological activity of a variety of analogs has defined some of the essential structural elements required for vitamin D activity. These structure-function relationships of analogs of 1α,25-(OH) 2-D 3 are also discussed with particular emphasis on the A-ring conformation. It is emphasized that the A-ring of these seco-steroids consist of a pair of rapidly equilibrating chair conformers. As a consequence, different chair conformations produce different orientations of substituent groups in the A-ring. It is proposed that the 1α-hydroxyl of 1α,25-dihydroxyvitamin D 3 or its geometric equivalent in analogs must occupy the equatorial as opposed to the axial orientation for optimization of biological activity.