title: Differential catabolism of 22-oxacalcitriol and 1,25-dihydroxyvitamin D3 by normal human peripheral monocytes.
abstract: 22-Oxacalcitriol [1,25-(OH)2-22oxa-D3] mimics the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in a variety of target tissues, including the systemic control of calcitriol metabolism. Similar to 1,25-(OH)2D3, 1,25-(OH)2-22oxa-D3 decreases the rate of 1,25-(OH)2D3 synthesis and accelerates its metabolic clearance rate. We have previously shown that in normal human monocytes, physiological concentrations of 1,25-(OH)2D3 and 1,25-(OH)2-22oxa-D3 determine identical suppression of 1,25-(OH)2D3 synthesis. Moreover, both sterols have a similar potency to induce vitamin D degradation through stimulation of the C24-hydroxylation pathway. In this study, we examined the ability of normal human monocytes to metabolize 1,25-(OH)2-22oxa-D3 and whether the enzymes involved are the same as those that catabolize 1,25-(OH)2D3. Time-course experiments demonstrated no detectable basal catabolic activity. However, exogenous 1,25-(OH)2D3 at physiological concentrations induced 1,25-(OH)2-22oxa-D3 degradation by normal human monocytes. Competition experiments showed that a 10-fold molar excess of unlabeled 1,25-(OH)2D3 inhibited tritiated-1,25-(OH)2-22oxa-D3 catabolism by 85%, whereas a 10-fold excess of unlabeled 1,25-(OH)2-22oxa-D3 reduced tritiated-1,25-(OH)2-22oxa-D3 catabolism by 33%. In contrast, although a 10-fold excess of unlabeled 1,25-(OH)2D3 reduced tritiated 1,25-(OH)2D3 catabolism by 60%, a 1000-fold excess of 1,25-(OH)2-22oxa-D3 was required to reduce tritiated 1,25-(OH)2D3 catabolism to this degree. The apparent Km for 1,25-(OH)2-22oxa-D3 was significantly higher than that of 1,25-(OH)2D3 (2.0 +/- 0.8 0.9 +/- 0.2 nM, respectively; P < 0.001) for the catabolic pathway induced by physiological concentrations of 1,25-(OH)2D3. Moreover, the presence of 0.65 nM 1,25-(OH)2D3 caused an additional increase in the Km for 1,25-(OH)2-22oxa-D3 (3.2 +/- 0.8 nM). These data suggest that 1,25-(OH)2-22oxa-D3 may be less accessible than 1,25-(OH)2D3 to the hydroxylases involved in vitamin D catabolism. The resulting prolonged biological half-life of the analog in certain target tissues may be involved in its selectivity.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: S
authors.initials: S
authors.lastname: Kamimura
authors.forename: M
authors.initials: M
authors.lastname: Gallieni
authors.forename: N
authors.initials: N
authors.lastname: Kubodera
authors.forename: Y
authors.initials: Y
authors.lastname: Nishii
authors.forename: A J
authors.initials: AJ
authors.lastname: Brown
authors.forename: E
authors.initials: E
authors.lastname: Slatopolsky
authors.forename: A
authors.initials: A
authors.lastname: Dusso
mesh_terms: D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000097:blood*; D006801:Humans; D007700:Kinetics; D009000:Monocytes / Q000378:metabolism*; D012016:Reference Values; D013997:Time Factors
chemical_list: D002117:Calcitriol; C051883:maxacalcitol