Enhanced biological activity of 1α,25-dihydroxy-20-epi-vitamin D 3, the C-20 epimer of 1α,25-dihydroxyvitamin D 3, is in part due to its metabolism into stable intermediary metabolites with significant biological activity

Abstract

1α,25-Dihydroxy-20-epi-vitamin D 3 (1α,25(OH) 2-20-epi-D 3), the C-20 epimer of the natural hormone 1α,25(OH) 2D 3, is several fold more potent than the natural hormone in inhibiting cell growth and inducing cell differentiation. At present, the various mechanisms responsible for the enhanced biological activities of this unique vitamin D 3 analog are not fully understood. In our present study we compared the target tissue metabolism of 1α,25(OH) 2D 3 with that of 1α,25(OH) 2-20-epi-D 3 using the technique of isolated perfused rat kidney. The results indicated that the C-24 oxidation pathway plays a major role in the metabolism of both compounds in the rat kidney. However, it was noted that the concentrations of two of the intermediary metabolites of 1α,25(OH) 2-20-epi-D 3, namely, 1α,24( R),25(OH) 3-20-epi-D 3 and 1α,25(OH) 2-24-oxo-20-epi-D 3 in the kidney perfusate, exceeded the concentrations of the corresponding intermediary metabolites of 1α,25(OH) 2D 3. Furthermore, 1α,25(OH) 2-24-oxo-20-epi-D 3 induces the conformation of the vitamin D receptor similar to that induced by its parent analog and is nearly as potent as its parent in inducing transactivation of a gene construct containing the human osteocalcin vitamin D-responsive element. We conclude that 1α,25(OH) 2-20-epi-D 3 by itself is not metabolically stable when compared to 1α,25(OH) 2D 3, but it acquires its metabolic stability because of the reduced rate of catabolism of its intermediary metabolites. Furthermore, 1α,25(OH) 2-24-oxo-20-epi-D 3, the stable bioactive intermediary metabolite plays a significant role in generating the enhanced biological activities ascribed to 1α,25(OH) 2-20-epi-D 3.