735 Antifibrogenic activities of novel vitamin D3 derivatives are altered in human fibroblasts expressing low vitamin D receptor or CYP27B1 enzyme

The vitamin D receptor (VDR) serves as a for active hydroxyderivatives. formation of hydroxyderivatives requires the presence specific cytochrome P450 (CYP) enzymes metabolism. These can be further hydroxylated by CYP27B1 at C1α-position which increases their affinity VDR. However, role in antiproliferative and antifibrotic activities CYP11A1-derived D3-metabolites is unknown. We tested action chemically synthesized derivatives: 20,23(OH2D3, 1,20(OH)2D3, or 1,20,23(OH)3D3 compared to 1,25(OH)2D3 20(OH)D3 (non-calcemic compound). Human fibroblasts were isolated freshly form neonatal skin used treatment with derivatives. Tested D3 derivatives inhibited proliferation decreased collagen production similar degree 20(OH)D3. Profibrotic are confirmed determining gene expressions, such Serpine 1 TGFB1, downregulated, stimulating MMP1 gene, respectively. ShRNA siRNA was silence expression VDR enzyme fibroblasts. results showed that diminished lacking effects also reduced deficient cells treated 20,23(OH)2D3. Therefore, we conclude dependent on