On the Mechanisms for the Selective Action of Vitamin D Analogs*

Dusso, Adriana; Negrea, Lavinia; Gunawardhana, S.; Lopez-Hilker, Silvia; Finch, Jane; Mori, Takashi; Nishii, Yasuho; Slatopolsky, Eduardo; Brown, Alex

doi:10.1210/endo-128-4-1687

Cited by 128 publications

(43 citation statements)

References 31 publications

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“…The reported in vitro (Table 1) and in vivo biological effects of OCT (7,(28)(29)(30)(31) and the data presented here with respect to its effect on VDR half-life and VDR conformation (Figs. 2, 3, and 5) show that substitution of the C-22 by an oxygen atom results in an analog that mimics most of the activities of 1,25-(OH)2vitamin D3.…”

Section: Discussionmentioning

confidence: 74%

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

Bemd

Pols

Birkenhäger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The 1,25-dihydroxyvitamin D3 [1,2vitamin D3] analog KH1060 exerts very potent effects on cell proliferation and cell differentiation via the vitamin D receptor (VDR). However, the activities of KH1060 are not associated with an increased affinity for the VDR. We now show that increased stabilization of the VDR-KH1060 complex could be an explanation for its high potencies. VDR half-life studies performed with cycloheximide-translational blocked rat osteoblast-like ROS 17/2.8 cells demonstrated that, in the absence of ligand, VDR levels rapidly decreased. After 2 hr, less than 10% of the initial VDR level could be measured. In the presence of 1,25-(OH)2vitamin D3, the VDR half-life was 15 hr. After 24 hr, less than 20% of the initial VDR content was detectable, whereas, at this time-point, when the cells were incubated with KH1060 80% of the VDR was still present. Differences in 1,25-(OH)2vitamin D3-and KH1060-induced conformational changes of the VDR could underlie the increased VDR stability. As assessed by limited proteolytic digestion analysis, both 1,25-(OH)2vitamin D3 and KH1060 caused a specific conformational change of the VDR. Compared with 1,25-(OH)2vitamin D3, KH1060 induced a conformational change that led to a far more dramatic protection of the VDR against proteolytic degradation. In conclusion, the altered VDR stability and the possibly underlying change in VDR conformation caused by KH1060 could be an explanation for its enhanced bioactivity.Besides the traditional effects on calcium and phosphate metabolism (1), the effects of 1,25-dihydroxyvitamin D3 [1,25-(OH)2vitamin D3] on cellular differentiation and proliferation and on immunological processes (2) might have relevance for the treatment of hyperproliferative and autoimmune diseases. However, the side effects (hypercalcemia and hypercalciuria) induced by the high doses needed to achieve these effects limit the use of 1,25-(OH)2vitamin D3 in clinical practice. This has prompted the development of new 1,25-(OH)2vitamin D3 analogs with reduced calcemic activity.Previous studies have shown that modifications in the side chain of the 1,25-(OH)2vitamin D3 molecule can lead to far more potent analogs. One of the most potent analogs until now, 20-Epi-22-oxa-24a,26a,27a-tri-homo-1,25-(OH)2vitamin D3 (KH1060) (3), is a strong inhibitor of tumor cell growth (4, 5) and an inducer of cell differentiation (4, 6, 7). KH1060 also exhibits strong immunosuppressive activity in both in vitro and in vivo studies (4,8,9). Furthermore, KH1060 is more potent than 1,25-(OH)2vitamin D3 in stimulating in vivo and in vitro bone resorption and osteoclast recruitment in murine bone marrow cultures (4,7,10).The differences in biological activity between 1,25-(OH)2vitamin D3 and KH1060 could not be explained by an increased affinity for the vitamin D receptor (VDR) (4, 5, 7). However, the presence of a (functional) VDR is essential for the biological responses of 1,25-(OH)2vitamin D3 and KH1060 (7,11,12). It is known that, through binding to the VDR, 1,25-(OH)2vitam...

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Section: Discussionmentioning

confidence: 74%

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

Bemd

Pols

Birkenhäger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…Generally, these analogues have been screened in terms of the affinity for the VDR and vitamin D-binding protein. Certain synthetic analogues like 22-oxa-1␣,25(OH) 2 D 3 appear to succeed in the dissection of various effects of 1␣,25(OH) 2 D 3 by taking advantage of the difference in binding to the VDR and vitamin D-binding protein and metabolic pathway (14). To date, however, no anti-vitamin D compounds that oppose the genomic actions of the natural ligand 1␣,25(OH) 2 D 3 , have been reported (13).…”

mentioning

confidence: 99%

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Ozono

Saito

Miura

et al. 1999

Journal of Biological Chemistry

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5). The effects exerted via the VDR are called genomic effects, in contrast to non-genomic effects, which means that 1␣,25(OH) 2 D 3 acts within a short period without transcription of target genes (6). The VDR-mediated effects of 1␣,25(OH) 2 D 3 in vivo are well known, since there is a human disease associated with the abnormality of the VDR gene, which is called vitamin D dependence type II (7). In addition, a mouse model of the disease was generated by targeting the VDR gene and has been used the analysis of the VDR function in vivo (8, 9).The VDR consists of several functional domains such as DNA-binding and ligand-binding domains (1, 2). Heterodimerization of the VDR with retinoid X receptor (RXR) is also important for the binding to a vitamin D-responsive element (VDRE) with high affinity (1, 2, 5, 10). Ligand-dependent activation of transcription requires the extreme C-terminal portion of the VDR, which is designated as the AF-2 core domain (1,11,12). The interaction of these domains is required for the VDR to regulate the transcription of target genes.A large number of 1␣,25(OH) 2 D 3 analogues have been synthesized in an attempt to dissociate various biological activities including hypercalcemic effects, bone-forming effects, and promotion of cell differentiation (for review, see Ref. . Although this differentiation is believed to be mediated by VDR, more direct evidence is needed to establish whether TEI-9647 is an antagonist of the genomic action of vitamin D. Antagonists, if obtained, would be useful for determining whether each of the effects of 1␣,25(OH) 2 D 3 is mediated by the VDR. In addition, a potentially promising way to achieve the differential effect of vitamin D is to use analogues that antagonize particular effects elicited by vitamin D.In contrast to the case of VDR, several antagonists have been reported for other members of the nuclear hormone receptor superfamily, and have contributed to the understanding of the

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“…Of greatest importance is its diminished affinity for DBP which is only one incident of hypercalcemia (calcium ?11.2 mg/ dl) was detected. The serum phosphate levels were un-approximately 500 times less than that of 1,25(OH) 2 D 3 [14,15]. This greatly alters the pharmacokinetics of the changed by 1 (OH)D 2 therapy and the dose of phosphate binders was not altered during the treatment analog.…”

Section: Development Of Vitamin D Analogs For Secondary Hyperparathyrmentioning

confidence: 95%

“…maximal levels (C max ) in the blood when administered intraperitoneally [14,16,17]. Despite the lower C max , the The major pathology associated with hyperparathyroidism is high turnover bone disease.…”

Section: Development Of Vitamin D Analogs For Secondary Hyperparathyrmentioning

confidence: 99%

Vitamin D Analogs: Perspectives for Treatment

Brown

Slatopolsky

1999

Mineral Electrolyte Metab

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Vitamin D therapy is widely used for the treatment of secondary hyperparathyroidism associated with chronic renal failure. However, administration of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] or its precursor 1α(OH)D₃, especially in combination with calcium-based phosphate binders, often produces hypercalcemia. Several vitamin D analogs have been developed that retain the direct suppressive action of 1,25(OH)₂D₃ on the parathyroid glands but have less calcemic activity. These analogs offer a safer and more effective means of controlling secondary hyperparathyroidism. 22-Oxa-1,25(OH)₂D₃ (22-oxacalcitriol or OCT), 19-nor-1,25(OH)₂D₂ (19-norD₂) and 1α(OH)D₂ have been tested in animal models of uremia and in clinical trials. Intravenous 19-norD₂ and oral 1α(OH)D₂ have been approved for use in the United States; OCT is currently under review. The mechanisms by which these analogs exert their selective actions on the parathyroid glands are under investigation. The low calcemic activity of OCT has been attributed to its rapid clearance which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression. The selectivity of 19-norD₂ and 1α(OH)D₂ is achieved by a distinct mechanism(s). Knowledge of how these compounds exert their selective actions on the parathyroid glands may allow the design of more effective analogs in the future.

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On the Mechanisms for the Selective Action of Vitamin D Analogs*

Cited by 128 publications

References 31 publications

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Vitamin D Analogs: Perspectives for Treatment

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