Quach Holly P, Dzekic Tamara, Bukuroshi Paola, Pang K Sandy
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Biopharm Drug Dispos. 2018 Apr;39(4):196-204. doi: 10.1002/bdd.2126.
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.
评估了维生素D以及合成维生素D类似物1α-羟基维生素D[1α(OH)D]、1α-羟基维生素D[1α(OH)D]和25-羟基维生素D[25(OH)D]在体内作为小鼠降胆固醇药物的维生素D受体（VDR）相关活性。这些前体在体内被激活：1α(OH)D和1α(OH)D分别由肝脏CYP2R1和CYP27A1转化为活性VDR配体1α,25-二羟基维生素D[1,25(OH)D]和1α,25-二羟基维生素D[1,25(OH)D]。1α(OH)D也可能被CYP24A1激活为另一种活性VDR配体1α,24-二羟基维生素D[1,24(OH)D]。25(OH)D是维生素D在肝脏中经CYP2R1和/或CYP27A1形成的代谢产物，在肾脏中被CYP27B1激活为1,25(OH)D。在喂食高脂肪/高胆固醇西方饮食3周的C57BL/6小鼠中，在饮食的最后一周每隔一天腹腔注射维生素D类似物。通过抑制小鼠肝脏小异二聚体伴侣（Shp）和增加胆固醇7α-羟化酶（Cyp7a1）表达实现的降胆固醇排序为：1.75 nmol/kg 1α(OH)D > 1248 nmol/kg 25(OH)D（剂量比为0.0014）>> 1625 nmol/kg维生素D。除了1.21 nmol/kg 1α(OH)D未能降低肝脏和血浆胆固醇含量外，在前体形成后肝脏中1,25(OH)D的浓度与肝脏胆固醇水平之间观察到显著的负相关。综合结果表明，维生素D类似物1α(OH)D和25(OH)D在激活为1,25(OH)D后具有降胆固醇特性：在小鼠中，1α(OH)D被肝脏酶快速激活，25(OH)D被肾脏Cyp27b1缓慢激活。
