Abstract
Since our original demonstration of the metabolism of 1α,25(OH)~2~D~3~ into 1α,25(OH)~2~‐3‐epi‐D~3~ in human keratinocytes, there have been several reports indicating that epimerization of the 3 hydroxyl group of vitamin D compounds is a common metabolic process. Recent studies reported the metabolism of 25OHD~3~ and 24(R),25(OH)~2~D~3~ into their respective C‐3 epimers, indicating that the presence of 1α hydroxyl group is not necessary for the 3‐epimerization of vitamin D compounds. To determine whether the presence of a 25 hydroxyl group is required for 3‐epimerization of vitamin D compounds, we investigated the metabolism of 1αOHD~3~, a non‐25 hydroxylated vitamin D compound, in rat osteosarcoma cells (ROS 17/2.8). We noted metabolism of 1αOHD~3~ into a less polar metabolite which was unequivocally identified as 1αOH‐3‐epi‐D~3~ using the techniques of HPLC, GC/MS, and ^1^H‐NMR analysis. We also identified 1αOH‐3‐epi‐D~3~ as a circulating metabolite in rats treated with pharmacological concentrations of 1αOHD~3~. Thus, these results indicated that the presence of a 25 hydroxyl group is not required for 3‐epimerization of vitamin D compounds. Furthermore, the results from the same studies also provided evidence to indicate that 1αOH‐3‐epi‐D~3~, like 1αOHD~3~, is hydroxylated at C‐25. We then evaluated the biological activities of 1αOH‐3‐epi‐D~3.~ Treatment of normal rats every other day for 7 days with 2.5 nmol/kg of 1αOH‐3‐epi‐D~3~ did not raise serum calcium, while the same dose of 1αOHD~3~ increased serum calcium by 3.39 ± 0.52 mg/dl. Interestingly, in the same rats which received 1αOH‐3‐epi‐D~3~ we also noted a reduction in circulating PTH levels by 65 ± 7%. This ability of 1αOH‐3‐epi‐D~3~ to suppress PTH levels in normal rats without altering serum calcium was further tested in rats with reduced renal function. The results indicated that the ED50 of 1αOH‐3‐epi‐D~3~ for suppression of PTH was only slightly higher than that of 1α,25(OH)~2~D~3~, but that the threshold dose of the development of hypercalcemia (total serum Ca > 10.5 mg/dl) was nearly 80 times higher. These findings indicate that 1αOH‐3‐epi‐D~3~ is a highly selective vitamin D analog with tremendous potential for treatment of secondary hyperparathyroidism in chronic renal failure patients. © 2005 Wiley‐Liss, Inc.