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, calc itroic 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 ex perimental 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 alter nate days, starting 3 days prior and for up to 5 days post immunizatio n 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 h ypercalcemia 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 th at 1,25-(OH)(2)-24OXO-16eneD3(,) a stable intermediary metabolite of t he vitamin D analog, 1,25-(OH)(2)-16eneD(3) exerts immunosuppressive a ctivity equal to its parent without causing hypercalcemia in vivo.