title: Targeted delivery of vitamin D to the colon using β-glucuronides of vitamin D: therapeutic effects in a murine model of inflammatory bowel disease.
abstract: 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D] has been shown to inhibit development of dextran sodium sulfate (DSS)-induced colitis in mice but can also cause hypercalcemia. The aim of this study was to evaluate whether β-glucuronides of vitamin D could deliver 1,25(OH)(2)D to the colon to ameliorate colitis while reducing the risk of hypercalcemia. Initial studies demonstrated that bacteria residing in the lower intestinal tract were capable of liberating 1,25(OH)(2)D from 1,25-dihydroxyvitamin D(3)-25-β-glucuronide [β-gluc-1,25(OH)(2)D]. We also determined that a much greater upregulation of the vitamin D-dependent 24-hydroxylase gene (Cyp24) was induced in the colon by treatment of mice with an oral dose of β-gluc-1,25(OH)(2)D than 1,25(OH)(2)D, demonstrating targeted delivery of 1,25(OH)(2)D to the colon. We then tested β-glucuronides of vitamin D in the mouse DSS colitis model in two studies. In mice receiving DSS dissolved in distilled water and treated with 1,25(OH)(2)D or β-gluc-1,25(OH)(2)D, severity of colitis was reduced. Combination of β-gluc-1,25(OH)(2)D with 25-hydroxyvitamin D(3)-25-β-glucuronide [β-gluc-25(OH)D] resulted in the greatest reduction of colitis lesions and symptoms in DSS-treated mice. Plasma calcium concentrations were lower in mice treated with β-gluc-1,25(OH)(2)D alone or in combination with β-gluc-25(OH)D than in mice treated with 1,25(OH)(2)D, which were hypercalcemic at the time of death. β-Glucuronides of vitamin D compounds can deliver 1,25(OH)(2)D to the lower intestine and can reduce symptoms and lesions of acute colitis in this model.
authors: College of Veterinary Medicine, Iowa State Univ., Ames, IA 50011, USA. jpgoff@iastate.edu
authors: Jesse P
authors: JP
authors: Goff
authors: Nicholas J
authors: NJ
authors: Koszewski
authors: Joseph S
authors: JS
authors: Haynes
authors: Ronald L
authors: RL
authors: Horst
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D003092:Colitis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004337:Drug Carriers; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016896:Treatment Outcome; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D004337:Drug Carriers; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; C034777:1,25-dihydroxyvitamin D3 monoglucuronide; D002117:Calcitriol; D002118:Calcium