title: The effects of MC903 on 1,25-(OH)2D3 receptor binding, 24-hydroxylase activity and in vitro bone resorption.
abstract: MC903, a new vitamin D analog has been shown to exert potent effects on cell proliferation and differentiation, while in vivo a decreased activity on calcium metabolism has been observed. In the osteoblast-like cell line UMR-106, MC903 displaces tritiated 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) from its receptor at least as efficiently as 1,25-(OH)2D3. The effect of MC903 on 1,25-(OH)2D3 receptor up-regulation in UMR-106 cells and on bone resorption in fetal mouse radii/ulnae was comparable to that of 1,25-(OH)2D3. MC903 was about 50% less effective in inducing 24-hydroxylase activity and the subsequent C24-side chain oxidation of 25-(OH)D3 compared to 1,25-(OH)2D3. Ketoconazole did not potentiate MC903-induced 1,25-(OH)2D3 receptor up-regulation as was found with 1,25-(OH)2D3 which suggests that the C24-oxidation plays a minor role in the inactivation of MC903. Nevertheless, the comparable effects of MC903 and 1,25-(OH)2D3 on in vitro bone resorption indicate that the lower effectivity of MC903 on bone calcium mobilization in vivo has to be due to a higher metabolic clearance rate.
authors.affiliation: Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.
authors.forename: H A
authors.initials: HA
authors.lastname: Pols
authors.forename: J C
authors.initials: JC
authors.lastname: Birkenhäger
authors.forename: J P
authors.initials: JP
authors.lastname: Schilte
authors.forename: M P
authors.initials: MP
authors.lastname: Bos
authors.forename: J P
authors.initials: JP
authors.lastname: van Leeuwen
mesh_terms: D000818:Animals; D001665:Binding Sites; D001862:Bone Resorption / Q000503:physiopathology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; C055085:calcipotriene; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D007654:Ketoconazole; D002118:Calcium