Stereochemistry and Biological Activity of 1α,23,25-Trihydroxy-24-Oxo-Vitamin D₃, a Natural Metabolite of 1α,25-Dihydroxyvitamin D₃ † 413

The secosteroid hormone 1α,25(OH)₂-vitamin D₃ is metabolized into several intermediary metabolites before its final inactivation in various target tissues. At present the biological role of these intermediary metabolites is not completely understood. In our present study we evaluated the biological activity of 1α,23,25(OH)₃-24-oxo-vitamin D₃ which was previously identified as one of the major natural metabolites of 1α,25(OH)₂D₃. We first identified the formation of this metabolite in rat kidney, neonatal human keratinocytes and bovine parathyroid cells. The C(23) stereochemistry of the natural 1α,23,25(OH)₃-24-oxo-vitamin D₃ produced in these various tissues was determined to be S through the chemical synthesis of the C(23) epimers of 1α,23,25(OH)₃-24-oxo D₃. The biological activity of 1α,23(S),25(OH)₃-24-oxo-vitamin D₃ in primary cultures of bovine parathyroid cells is determined by comparing the potency of this metabolite to that of 1α,25(OH)₂D₃ in suppression of parathyroid hormone (PTH) secretion. The results indicate that 1α,23(S),25(OH)₃-24-oxo-vitamin D₃ potently suppresses PTH secretion even at concentrations as low as 10^-12 M. While 1α,23(S),25(OH)₃-24-oxo-vitamin D₃ only appeared to be slightly less active than 1α (OH)₂D₃, the difference is not significant. The relatively high activity of 1α,23(S),25(OH)₃-24-oxo-vitamin D₃ cannot be explained on the basis of its affinity for the vitamin D receptor as the metabolite is found to be less effective than radio inert 1α,25(OH)₂D₃ in blocking the uptake and receptor binding of [³H] 1α,25(OH)₂D₃ in intact parathyroid cells. Further studies are required to explain the molecular basis for the activity of 1α,23(S),25(OH)₃-24-oxo-vitamin D₃ in its ability to suppress PTH secretion. At present it is the general belief that the target tissue metabolism of 1α,25(OH)₂D₃ into various intermediary metabolites is only a process of catabolism. However, our present study indicates that some of the intermediary metabolites of 1α,25(OH)₂D₃, may indeed possess significant biological activities of their own.