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

1 alpha,25-Dihydroxy-20-epi-vitamin D-3 (1 alpha,25(OH)(2)-20-epi-D-3), the C-20 epimer of the natural hormone 1 alpha,25(OH)(2)D-3, is several fold m ore potent than the natural hormone in inhibiting cell growth and inducing cell differentiation. At present, the various mechanisms responsible for th e enhanced biological activities of this unique vitamin D-3 analog are not fully understood. In our present study we compared the target tissue metabo lism of 1 alpha,25(OH)(2)D-3 with that of 1 alpha,25(OH)(2)-20-epi-D-3 usin g 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 co mpounds in the rat kidney. However, it was noted that the concentrations of two of the intermediary metabolites of 1 alpha,25(OH)(2)-20-epi-D-3, namel y, 1 alpha,24(R),25(OH)(3)-20-epi-D-3 and 1 alpha,25(OM)(2)-24-oxo-20-epi-D -3 in the kidney perfusate, exceeded the concentrations of the correspondin g intermediary metabolites of 1 alpha,25(OH)(2)D-3. Furthermore, 1 alpha,25 (OH)(2)-24-oxo-20-epi-D-3 induces the conformation of the vitamin D recepto r similar to that induced by its parent analog and is nearly as potent as i ts parent in inducing transactivation of a gene construct containing the hu man osteocalcin vitamin D-responsive element. We conclude that 1 alpha,25(O H)(2)-20-epi-D-3 by itself is not metabolically stable when compared to 1 a lpha,25(OH)(2)D-3, but it acquires its metabolic stability because of the r educed rate of catabolism of its intermediary metabolites. Furthermore, 1 a lpha,25(OH)(2)-24-oxo-20-epi-D-3, the stable bioactive intermediary metabol ite plays a significant role in generating the enhanced biological activiti es ascribed to 1 alpha,25(OH)(2)-20-epi-D-3. (C) 2000 Elsevier Science Ltd. All rights reserved.