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Modification of 1 alpha,25-dihydroxyvitamin D3 metabolism by introduction of 26,26,26,27,27,27-hexafluoro atoms in human promyelocytic leukaemia (HL-60) cells: isolation and identification of a novel bioactive metabolite, 26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3.

ABSTRACT: To study whether the introduction of fluoro atoms into C-26 and C-27 positions on the 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] molecule could affect metabolism in human promyelocytic leukaemia (HL-60) cells, we compared the metabolism of 26,26,26,27,27,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 [26,27-F6-1 alpha,25(OH)2D3] and 1 alpha,25(OH)2D3 in HL-60 cells. 26,27-F6-1 alpha,25(OH)2D3 was mainly converted into a new bioactive metabolite, 26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25- trihydroxyvitamin D3 [26,27-F6-1 alpha,23(S),25(OH)3D3], but not into 26,26,26,27,27,27-hexafluoro-1 alpha,24(R),25-trihydroxyvitamin D3 [26,27-F6-1 alpha,24(R),25(OH)3D3] in HL-60 cells. 26,27-F6-1 alpha,23(S),25(OH)3D3 was identified by combinations of h.p.l.c., u.v. spectroscopy and g.c.-mass spectrometry. Evidence is presented that 26,27-F6-1 alpha,25(OH)2D2 was metabolized to 26,27-F6-1 alpha,23(S),25(OH)3D3 by C-23 hydroxylation as a first step of the metabolism, and the 23-hydroxylated bioactive metabolite was accumulated in the cells, whereas 1 alpha,25(OH)2D3 was initially deactivated and metabolized to 1 alpha,24(R),25(OH)3D3 by C-24 hydroxylation through a side-chain oxidation pathway resulting in C23-C24 cleavage, yielding 24,25,26,27-tetranor-1 alpha,23(OH)2D3 in HL-60 cells. These results show that 26,27-F6-1 alpha,25(OH)2D3 and 1 alpha,25(OH)2D3 are metabolized by different metabolic pathways in HL-60 cells.

SUBMITTER: Honda A

PROVIDER: S-EPMC1134909 | biostudies-other | 1993 Oct

REPOSITORIES: biostudies-other

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Project description:Background and objectivesElevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking.Design, setting, participants, & measurementsAn open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D-insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters.ResultsVitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9-25.6 ng/ml] for controls versus 12.6 ng/ml [6.9-41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9-47.2 ng/ml] for controls versus 39.9 ng/ml [31.5-44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3-141.6 pg/ml] for controls versus 101.1 pg/ml [74.2-123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis.ConclusionsPatients with CKD exhibit an altered ability to increase serum 24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.

Dataset Information

Modification of 1 alpha,25-dihydroxyvitamin D3 metabolism by introduction of 26,26,26,27,27,27-hexafluoro atoms in human promyelocytic leukaemia (HL-60) cells: isolation and identification of a novel bioactive metabolite, 26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3.

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