The effect of 22-oxacalcitriol on serum calcitriol.

Dusso, Adriana; Negrea, Lavinia; Finch, Jane; Kamimura, Shigehito; Lopez-Hilker, Silvia; Mori, Takashi; Nishii, Y; Brown, Alex; Slatopolsky, Eduardo

doi:10.1210/endo.130.6.1597134

Cited by 24 publications

(8 citation statements)

References 3 publications

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“…Thus, it is possible that in addition to being susceptible to attack by vitamin D-inducible enzymes in classical vitamin D target cells, OCT is also attacked by more general enzymes in the liver leading to cleavage of the side chain by similar or slightly different mechanisms. It is clear from the studies presented here that OCT is more efficiently degraded by vitamin D-target cells than by hepatoma cells, and this may be important to the in vivo distribution and biological activity of the drug (33) as well as to the endogenous ligand (34).…”

Section: -Oxacalcitriol Metabolismmentioning

confidence: 95%

In Vitro Metabolism of the Vitamin D Analog, 22-Oxacalcitriol, Using Cultured Osteosarcoma, Hepatoma, and Keratinocyte Cell Lines

Masuda

Byford

Kremer

et al. 1996

Journal of Biological Chemistry

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1 has potent cell differentiating/anti-proliferative activities in addition to its role in calcium homeostasis (1). This has led researchers in both universities and the pharmaceutical industry to search for so-called "noncalcemic" vitamin D analogs with accentuated differentiating/anti-proliferative properties and reduced ability to cause hypercalcemia (2, 3). 22-Oxacalcitriol (OCT) 2 was an early analog developed for this purpose and contains a 22-oxygen atom that replaces the 22-carbon of calcitriol. OCT binds to the chicken vitamin D receptor (VDR) with an approximately 8 times lower affinity than 1␣,25-(OH) 2 D 3 (4). However, OCT is 10 times more effective than 1␣,25-(OH) 2 D 3 in suppressing cell growth and inducing differentiation of the mouse myelocytic leukemic cell, WEHI-3, in vitro (5). OCT also possesses an enhanced in vivo immunomodulatory potency in mice that is 50 times higher than that of 1␣,25-(OH) 2 D 3 (6). In contrast, OCT has reduced calcemic activity in vivo ( 1 ⁄50-1 ⁄100 that of 1␣, 25-(OH) 2 D 3 ), both in terms of mobilizing calcium from bone and in stimulating intestinal calcium transport in vitamin D-deficient and normal rats (7, 8). The mechanisms responsible for these differences in biological activity remain unclear, but factors such as cellular uptake and intracellular metabolism could contribute to these differences.OCT binds poorly to the vitamin D binding protein (DBP) and is transported in the plasma bound by lipoproteins (chylomicrons and low density lipoprotein) in vivo (9), and this leads to an unusual distribution pattern with a degree of concentration of the vitamin D analog in parathyroid tissue (10). In contrast, little is known about OCT metabolism except that it appears to be excreted as a glucuronide conjugate in the bile, possibly a derivative of a truncated version of OCT (10). Furthermore, there have been suggestions that a metabolite with a truncated side chain may be formed in bovine parathyroid cell cultures in vitro (11), although details of this have yet to be published.In these studies we set out to provide convincing physicochemical identification for metabolites generated in a variety of cultured cell models, namely the human hepatoma lines HepG2 and Hep3B (12), the rat osteosarcoma cell line UMR-106 (13), and the human keratinocyte cell lines HPK1A and HPK1A-ras (14, 15). Because these cell models mimic vitamin D metabolism found in vivo, we expected to observe the same metabolites found and in some cases tentatively identified by others (10, 11). In addition, our objective was to study the rate of OCT metabolism in various cell lines in order to gauge the involvement of vitamin D-inducible catabolic pathways as compared with more general metabolizing systems. Our results support the concept that OCT is subject to extensive metabolism in a variety of tissues that leads to side chain truncated forms excreted in the bile. * This work was partially supported by grants from the Medical Research Council of Canada (to G. J.). The costs of publication of this a...

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Section: -Oxacalcitriol Metabolismmentioning

confidence: 95%

In Vitro Metabolism of the Vitamin D Analog, 22-Oxacalcitriol, Using Cultured Osteosarcoma, Hepatoma, and Keratinocyte Cell Lines

Masuda

Byford

Kremer

et al. 1996

Journal of Biological Chemistry

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“…We have also shown that when peripheral blood monocytes were exposed to physiological concentrations of 1,25(OH) 2 D 3 , 1␣-hydroxylase activity is markedly suppressed. In addition, exogenous 1,25(OH) 2 D 3 promotes an induction of vitamin D catabolism by increasing 24-hydroxylase mRNA 2 and activity (22). Because both effects of the sterol require at least 2 h of exposure to 1,25(OH) 2 D 3 (22), it is likely that the inhibition of 1,25(OH) 2 D 3 production by 1,25(OH) 2 D 3 also involves a genomic mechanism.…”

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confidence: 99%

“…In addition, exogenous 1,25(OH) 2 D 3 promotes an induction of vitamin D catabolism by increasing 24-hydroxylase mRNA 2 and activity (22). Because both effects of the sterol require at least 2 h of exposure to 1,25(OH) 2 D 3 (22), it is likely that the inhibition of 1,25(OH) 2 D 3 production by 1,25(OH) 2 D 3 also involves a genomic mechanism. In the present studies, we used this human monocyte model to assess the physiological relevance of microtubule integrity in the response to 1,25(OH) 2 D 3 .…”

mentioning

confidence: 99%

Microtubules Mediate Cellular 25-Hydroxyvitamin D3 Trafficking and the Genomic Response to 1,25-Dihydroxyvitamin D3 in Normal Human Monocytes

Kamimura

Gallieni

Zhong

et al. 1995

Journal of Biological Chemistry

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It has been suggested recently that hormone-free glucocorticoid receptors are located predominantly in the cytoplasm, and, after the addition of steroid, they are rapidly translocated to the nucleus (3-6). The transfer of glucocorticoid receptor into the nucleus involves translocation along microtubules as revealed by immunofluorescent studies (7) in a process that is driven by tubulin-associated dynein motors (8).In the case of vitamin D, there is some controversy as to whether apoVDRs reside only in the nucleus like the thyroid hormone receptor (9) or whether they can undergo ligand-dependent translocation like the glucocorticoid receptor (10, 11). Using a recently developed fluorescent ligand, Barsony et al. (12) were able to demonstrate the cytoplasmic localization of the VDR in viable human skin fibroblasts, porcine kidney epithelial cells, human breast cancer cells, and rat osteosarcoma cells, supporting previous immunocytochemical findings in fixed human fibroblasts (13) and osteoblasts (14). Although immunocytology has shown that cytoplasmic VDR co-localizes with tubulin and that disruption of microtubular assembly blocks the translocation of the 1,25(OH) 2 D 3 -VDR complex into the nucleus (15) in microwave fixed fibroblasts, the role of microtubules on VDR transport in viable cells has never been evaluated. We hypothesized that if this intracellular transport system is of physiological relevance, the genomic response to 1,25(OH) 2 D 3 should be impaired with alterations in the structure or function of the microtubule network. We tested this hypothesis in normal human monocytes.Human monocytes express receptors for 1,25(OH) 2 D 3 that are indistinguishable from those described in classical 1,25(OH) 2 D 3 target tissues (16), and the interactions of 1,25(OH) 2 D 3 with monocytes-macrophages have critical implications for the regulation of immune responses (17)(18)(19)(20). Our laboratory has demonstrated that peripheral blood monocytes from normal individuals constitutively express 1␣-hydroxylase, the enzyme responsible for the conversion of 25-hydroxyvitamin D 3 (25(OH)D 3 ) to 1,25(OH) 2 D 3 (21). We have also shown that when peripheral blood monocytes were exposed to physiological concentrations of 1,25(OH) 2 D 3 , 1␣-hydroxylase activity is markedly suppressed. In addition, exogenous 1,25(OH) 2 D 3 promotes an induction of vitamin D catabolism by increasing 24-hydroxylase mRNA 2 and activity (22). Because both effects of the sterol require at least 2 h of exposure to 1,25(OH) 2 D 3 (22), it is likely that the inhibition of 1,25(OH) 2 D 3 production by 1,25(OH) 2 D 3 also involves a genomic mechanism. In the present studies, we used this human monocyte model to assess the physiological relevance of microtubule integrity in the response to 1,25(OH) 2 D 3 . This report demonstrates for the first time that integrity of the microtubule network is critical for a normal genomic response to 1,25(OH) 2 D 3 and that an intracel-* This work was supported in part by United States Public Health Service NIDDK, N...

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“…- 20 We suggest that the enhancing effect of OCT on pressor action may not be mediated through increasing 1,25(OH) 2 D 3 .…”

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confidence: 79%

Enhancement of vasoconstrictor response by a noncalcemic analogue of vitamin D3.

1993

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To clarify the effects of active vitamin D 3 on pressor and vascular responses to vasoconstrictor substances, we studied pressor responses to the intravenous injection of norepinephrine or angiotensin II (Ang II) and vasoconstrictor responses to norepinephrine. Sprague-Dawley rats were given 1,25 -dihydroxyvitamin D 3 subcutaneously (200 ng/kg per day) for 14 days. The administration of 1,25-dihydroxyvitamin D, augmented the pressor responses to norepinephrine and Ang II in conscious rats and was associated with a significant increase in serum calcium concentration (11.0±0.2 mg/dl). To further clarify whether the increased pressor response to vasoconstrictors may be due to the calcemic or direct action of active vitamin D 3 , we studied the effect of its noncalcemic analogue, 22-oxacalcitriol, and its inactive analogue, 24,25-dihydroxy vitamin D } , on the pressor response to vasoconstrictors in rats. The pressor responses to norepinephrine and Ang II were apparently augmented in 22-oxacalcitriol-treated rats similarly to 1,25-dihydroxyvitamin D 3 -treated rats. In contrast, the pressor responses were not affected by either 24,25-dihydroxy vitamin D 3 or the intravenous infusion of calcium chloride. In an ex vivo experiment using a mesenteric preparation, the vascular sensitivity to norepinephrine was moderately augmented in rats treated with both 22-oxacalcitriol and 1,25-dihydroxyvitamin D 3 but was not affected in rats treated with 24,25-dihydroxyvitamin D 3 . The results suggest that the enhanced pressor responses to norepinephrine and Ang II could be attributed to the direct effect of active vitamin D, on vasculature rather than to hypercalcemia. the calcemic effect of 1,25(OH) 2 D 3 might in some way contribute to the increased pressor action of the active vitamin D 3 . Elevation of serum calcium concentration in forearm blood flow with intrabrachial infusion of calcium not only increased basal forearm vascular resistance but also augmented the forearm vascular responses to vasoactive substances in humans.10 In addition to its calcemic effect, 1,25(OH) 2 D 3 has noncalcemic effects, such as stimulating cell differentiation," depressing parathyroid hormone, 12 and enhancing the immune response. 13 We therefore should consider both noncalcemic and calcemic effects as contributing to the vasoconstrictive action of 1,25(OH) 2 D 3 .There have been no previous studies on the noncalcemic action of 1,25(OH) 2 D 3 on vasculature. To evaluate whether noncalcemic effects of 1,25(OH) 2 D 3 may be involved in increased vasoconstrictor responses, we studied the effect of chronically administered 1,25-(OH) 2 D 3 , its noncalcemic analogue 22-oxacalcitriol (OCT), or its nonactive analogue 24,25 -dihydroxyvitamin D 3 [24,25(OH) 2 D 3 ] on the in vivo and ex vivo vascular responses to norepinephrine or angiotensin II (Ang II) in Sprague-Dawley rats. Methods Protocol 1Forty 8-week-old male Sprague-Dawley rats (body weight, 200-250 g; Charles River Japan, Atsugi, Japan) were subjected to continuous infusion of 200

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The effect of 22-oxacalcitriol on serum calcitriol.

Cited by 24 publications

References 3 publications

In Vitro Metabolism of the Vitamin D Analog, 22-Oxacalcitriol, Using Cultured Osteosarcoma, Hepatoma, and Keratinocyte Cell Lines

In Vitro Metabolism of the Vitamin D Analog, 22-Oxacalcitriol, Using Cultured Osteosarcoma, Hepatoma, and Keratinocyte Cell Lines

Microtubules Mediate Cellular 25-Hydroxyvitamin D3 Trafficking and the Genomic Response to 1,25-Dihydroxyvitamin D3 in Normal Human Monocytes

Enhancement of vasoconstrictor response by a noncalcemic analogue of vitamin D3.

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