1,25-DIHYDROXY-24-OXO-16ENE-VITAMIN-D3, A RENAL METABOLITE OF THE VITAMIN-D ANALOG 1,25-DIHYDROXY-16ENE-VITAMIN-D3, EXERTS IMMUNOSUPPRESSIVE ACTIVITY EQUAL TO ITS PARENT WITHOUT CAUSING HYPERCALCEMIA IN-VIVO

The hormone, 1,25-(OH)(2)D-3, is metabolized into 1,25-(OH)(2)-24-OXO-D-3, in kidney prior to conversion to its final inactive product, calcitroic acid. Similarly, 1,25-(OH)(2)-24OXO-16eneD,, is produced in the kidney from the Vitamin D analog, 1,25(OH)(2)-16eneD(3), but resists further hydroxylotion. nle analog's metabolite was synthesized and its biologic activity compared to the parent compound. Naive SJL/J mice, 4 weeks old, were immunized with neuroantigen in adjuvant to induce experimental autoimmune encephalomyelitis [EAE]. Treatment with 1,25-(OH)(2)-24OXO-16eneD(3) was given at 0.05, 0.15 and 0.3 ug I.P., on alternate days, starting 3 days prior and for up to 5 days post immunization and compared to a similar treatment with 0.1 ug 1,25-(OH)(2)D-3 or 1,25-(OH)(2)-16eneD(3). Suppression of EAE was observed with 0.15 ug 1,25(OH)(2)-24OXO-16eneD(3), comparable to the suppression induced with the parent compound and more potent than 1,25(OH)(2)D-3. However, no hypercalcemia was seen in mice treated with 0.15 ug of OXO-metabolite (9.7 +/- 0.6 vs 9.3 +/- 1.1 mg/dl, treated vs controls), in contrast to 1,25-(OH)(2)D-3 and 1,25-(OH)(2)-16eneD(3) (11.2 +/- 1.0 and 11.0 +/- 0.9 mg/dl respectively; p <0.001). In summary, our results suggest that 1,25-(OH)(2)-24OXO-16eneD3(,) a stable intermediary metabolite of the vitamin D analog, 1,25-(OH)(2)-16eneD(3) exerts immunosuppressive activity equal to its parent without causing hypercalcemia in vivo.