Potencies of vitamin D analogs, 1α-hydroxyvitamin D , 1α-hydroxyvitamin D and 25-hydroxyvitamin D , in lowering cholesterol in hypercholesterolemic mice in vivo.

Vitamin D and the synthetic vitamin D analogs, 1α-hydroxyvitamin D [1α(OH)D ], 1α-hydroxyvitamin D [1α(OH)D ] and 25-hydroxyvitamin D [25(OH)D ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D and 1α(OH)D are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D [1,25(OH) D ] and 1α,25-dihydroxyvitamin D [1,25(OH) D ] respectively. 1α(OH)D may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D [1,24(OH) D ], another active VDR ligand. 25(OH)D , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D , is activated by CYP27B1 in the kidney to 1,25(OH) D . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D  > 1248 nmol/kg 25(OH)D (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D . Except for 1.21 nmol/kg 1α(OH)D that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH) D formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D and 25(OH)D exhibit cholesterol lowering properties upon activation to 1,25(OH) D : 1α(OH)D is rapidly activated by liver enzymes and 25(OH)D is slowly activated by renal Cyp27b1 in mouse.