Novel metabolic pathways of vitamin D3 -: Identification of C-3 epimerization and C-25 dehydration pathways and biological activity of novel metabolites

The active form of vitamin D-3, 1alpha,25-dihydroxyvitamin D-3 [1alpha,25(OH)(2)D-3], functions to maintain calcium and phosphorus homeostasis and plays an important role in cell proliferation and differentiation. Since the discovery of non-classical functions of 1alpha,25(OH)(2)D-3, many 1alpha,25(OH)(2)D-3 analogs have been synthesized to separate calcemic properties from the antiproliferative cell-differentiating proper-ties. 1alpha,25(OH)(2)D-3 and its precursor, 25-hydroxyvitamin D-3[25(OH)D-3], are metabolized via C-24 and C-23/26 oxidation pathways. Recently, a novel A-ring modification metabolic pathway of I a,25(OH)2D3, the C-3 epimerization pathway, was identified. In our laboratory, C-3 epimerized metabolites of major natural vitamin D3 metabolites, 1alpha,25(OH)(2)D-3, 25(OH)D-3 and 24,25-dihydroxyvitamin D, [24,25(OH)(2)D-3], and a synthetic analog, 22-oxacalcitriol [22-oxa-1alpha,25(OH)(2)D-3, OCT], were identified. In addition, other novel metabolites of OCT were assigned to two kinds of C-25 dehydrates, 25-dehydroxy-25-ene-22-oxa-1alpha-hydroxyvitamin D-3 [25-ene-22-oxa-1alpha(OH)D-3] and 25-dehydroxy-24-ene-22-oxa-la-hydroxyvitamin D-3 [24-ene22-oxa-1alpha(OH)D-3]. In this mini-review, the identification of C-3 epimers of vitamin D-3 compounds and C-25 dehydrates of OCT using H-1-NMR and LC-MS techniques is described. Furthermore, the cell-specific generation and biological activity of these novel metabolites are reviewed.