Novel Metabolic Pathways of Vitamin D₃ — Identification of C-3 Epimerization and C-25 Dehydration Pathways and Biological Activity of Novel Metabolites

Abstract

The active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ [1α,25(OH)₂D₃], 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 1α,25(OH)₂D₃, many 1α,25(OH)₂D₃ analogs have been synthesized to separate calcemic properties from the antiproliferative cell-differentiating properties. 1α,25(OH)₂D₃ and its precursor, 25-hydroxyvitamin D₃ [25(OH)D₃], are metabolized via C-24 and C-23/26 oxidation pathways. Recently, a novel A-ring modification metabolic pathway of 1α,25(OH)₂D₃, the C-3 epimerization pathway, was identified. In our laboratory, C-3 epimerized metabolites of major natural vitamin D₃ metabolites, 1α,25(OH)₂D₃, 25(OH)D₃ and 24,25-dihydroxyvitamin D₃ [24,25(OH)₂D₃], and a synthetic analog, 22-oxacalcitriol [22-oxa-1α,25(OH)₂D₃, 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-1α-hydroxyvitamin D₃ [25-ene-22-oxa-1α(OH)D₃] and 25-dehydroxy-24-ene-22-oxa-1α-hydroxyvitamin D₃ [24-ene-22-oxa-1α(OH)D₃]. In this mini-review, the identification of C-3 epimers of vitamin D₃ compounds and C-25 dehydrates of OCT using ¹H-NMR and LC-MS techniques is described. Furthermore, the cell-specific generation and biological activity of these novel metabolites are reviewed.