Potencies of Vitamin D Analogs, 1 α‐Hydroxyvitamin D3, 1α‐Hydroxyvitamin D2, and 25‐Hydroxyvitamin D3, in Lowering Cholesterol in Hypercholesterolemic Mice in vivo

Abstract Vitamin D3 and the synthetic vitamin D analogs, 1α‐hydroxyvitamin D3 [1α(OH)D3] and 1α‐hydroxyvitamin D2 [1α(OH)D2], and 25‐hydroxyvitamin D3 [25(OH)D3] were appraised for their vitamin D receptor (VDR) associated‐potencies as cholesterol lowering agents in mice in vivo. These precursors require activation in vivo: 1α(OH)D3 and 1α(OH)D2 are activated by liver Cyp2r1 and Cyp27a1 to active VDR ligands, 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and 1α,25‐dihydroxyvitamin D2 [1,25(OH)2D2], respectively. 1α(OH)D2 may also be activated by Cyp24a1 to 1α,24‐dihydroxyvitamin D2 [1,24(OH)2D2], another active VDR ligand. 25(OH)D3, the metabolite formed via Cyp2r1 and Cyp27a1 in liver from vitamin D3, is activated by Cyp27b1 in the kidney to 1,25(OH)2D3. In C57BL/6 mice fed the high fat/high cholesterol Western diet (WD) for three 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 small heterodimer partner (Shp) lowering and increased cholesterol 7α‐hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D3 > 1248 nmol/kg 25(OH)D3 (dose ratio of 0.0014) >> 1625 nmol/kg vitamin D3. Except for 1.21 nmol/kg 1α(OH)D2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH)2D3 formed from the precursors and liver cholesterol levels. The compo...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL PAPER Source Type: research