The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion.

Brown, Alex; Ritter, Cindy; Finch, Jane; Morrissey, Jeremiah J.; Martin, Kévin; Murayama, E; Nishii, Y.; Slatopolsky, Eduardo

doi:10.1172/jci114229

Cited by 219 publications

(83 citation statements)

References 25 publications

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“…The most important etiologic factors of this resistance are markedly de- creased VDR and CaSR contents in PTC and severely swollen PTG as a result of hyperplasia. In dialysis patients, these agents not only decrease PTH levels but also improve the response to VD by VDR upregulation in PTC (17)(18)(19)(20)(21). A previous study showed that the CaSR mRNA expression level in PTG is dosedependently increased by 1,25-D 3 without any changes in PTH and Ca 2ϩ levels (22).…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

Shiizaki¹,

Negi²,

Hatamura

et al. 2005

Journal of the American Society of Nephrology

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The most important etiological factors of resistance to medical treatments for secondary hyperparathyroidism are the decreased contents of the vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in parathyroid cells and a severely swollen parathyroid gland (PTG) as a result of hyperplasia. The effects of direct maxacalcitol (OCT) injection into PTG in terms of these factors were investigated in this study. The PTG of Sprague-Dawley rats that were 5/6 nephrectomized and fed a high-phosphate diet were treated by a direct injection of OCT (DI-OCT) or vehicle (DI-vehicle). The changes in serum intact parathyroid hormone (PTH), Ca 2؉, and phosphorus levels, in VDR and CaSR expression levels in parathyroid cells, and in Ca 2؉ -PTH curves were examined. Apoptosis was analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and DNA electrophoresis for PTG. DI-OCT markedly decreased serum intact PTH level, and a significant difference in this level between DI-OCT and DI-vehicle was observed. However, serum Ca 2؉ and phosphorus levels did not changed markedly in both groups. The upregulations of both VDR and CaSR, the clear shift to the left downward in the Ca 2؉ -PTH curve, and the induction of apoptosis after DI-OCT were observed. These findings were not observed in the DI-vehicle-treated rats. Moreover, these effects of DI-OCT were confirmed by the DI-OCT into one PTG and DI-vehicle alone into another PTG in the same rat. DI-OCT may introduce simultaneous VDR and CaSR upregulations and the regression of hyperplastic PTG, and these effects may provide a strategy for strongly suppressing PTH levels in very severe secondary hyperparathyroidism. S econdary hyperparathyroidism (SHPT) resulting from ESRD causes not only renal osteodystrophy but also cardiovascular disorders because of ectopic calcification in vascular tissues. A low level of parathyroid hormone (PTH) causes adynamic bone disease; easily increases serum calcium (Ca), phosphorus (P), and CaϫP levels; and may contribute to a poor prognosis in patients with ESRD. Thus, the maintenance of appropriate levels of PTH, Ca, and P is required for the improvement of the prognosis and quality of life of these patients (1-3).SHPT develops in conditions of P retention, low Ca level, and the inactivation of vitamin D (VD) (4 -6); therefore, the control of P level and supplementations of Ca and VD are necessary in patients with SHPT as preventive or medical treatment. However, advanced SHPT with severely swollen parathyroid glands (PTG) as a result of hyperplasia is resistant to these medical treatments because of the low contents of VD receptor (VDR) and Ca-sensing receptor (CaSR) in parathyroid cells (PTC) (7,8). When SHPT progresses into such status, it is considered irreversible. Thus, patients with very severe SHPT require parathyroidectomy-autotransplantation (PTx-AT), which may be complicated by some problems, such as the necessity of general anesthesia, the hyperor hypofunction of autotransplanted PTG, and mental suffering.The ...

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Section: Discussionmentioning

confidence: 99%

Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

Shiizaki¹,

Negi²,

Hatamura

et al. 2005

Journal of the American Society of Nephrology

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“…Briefly, 2-mo-old rats were obtained from Jackson Laboratory and fed a normal rat chow for 2 wk (10,47) before they were divided into seven groups (6 animals per group) and injected with either vehicle (propylene glycol) or three concentrations (0.8, 2.0, and 4.0 g/kg) of 1,25(OH) 2D3 or 20(OH)D2 dissolved in propylene glycol, for 7 consecutive days. A day after the final dosing, selected organs including liver, kidney, heart, skin, and intestine were collected, fixed in 4% formalin and further processed to paraffin blocks.…”

Section: Testing Of Calcemic Effect and Histological Markers Of Toxicitymentioning

confidence: 99%

20-Hydroxyvitamin D₂ is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells

Slominski¹,

Kim²,

Tuckey

et al. 2011

American Journal of Physiology-Cell Physiology

105

221

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In vivo tests show that while 1,25(OH) 2D3 at doses as low as 0.8 g/kg induces calcium deposits in the kidney and heart, 20(OH)D 2 is devoid of such activity even at doses as high as 4 g/kg. Silencing of CY27B1 in human keratinocytes showed that 20(OH)D 2 does not require its transformation to 1,20(OH) 2D2 for its biological activity. Thus 20(OH)D2 shows cell-type dependent antiproliferative and prodifferentiation activities through activation of VDR, while having no detectable toxic calcemic activity, and is a poor substrate for CYP27B1. melanocytes; melanoma cells; keratinocytes; leukemia THE PHOTOCHEMICAL ISOMERIZATION of 7-dehydrocholesterol (7DHC) after absorption of UVB photons to the pre-vitamin D 3 intermediate, followed by its slow isomerization to three main products including D 3 , tachysterol, and lumisterol, represent the most

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“…Thus, during renal failure, the combination of lower levels of 1,25(OH) 2 D 3 and decreased binding of the available 1,25(OH) 2 D 3 to the parathyroid cells results in a marked increase in secretion of PTH at all levels of [Ca ion ]. This so-called "altered set point" for PTH secretion can be reversed by the administration of intravenous 1,25(OH) 2 D 3 (107,108) or vitamin D analogues (109). PTH is degraded principally in the liver and kidney into carboxy-terminal fragments, which are catabolized by the kidney (110 -112).…”

Section: Ckd In Patients Who Are Not On Dialysismentioning

confidence: 99%

“…When 1,25(OH) 2 D 3 is administered, especially with additional Ca from Ca-based phosphate binders, there is an increase in ␣ Ca , often leading to a positive ⌬ECF Ca and frank hypercalcemia (107)(108)(109).…”

Section: Ckd In Patients Who Are Not On Dialysismentioning

confidence: 99%

Contribution of Intestine, Bone, Kidney, and Dialysis to Extracellular Fluid Calcium Content

Bushinsky

2010

Clinical Journal of the American Society of Nephrology

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Calcium (Ca) balance is the net of Ca intake and output from the body over a period of time. The concept of Ca balance does not consider the redistribution of Ca that often occurs in patients with chronic kidney disease (CKD), especially those who are on dialysis, which is often in the form of soft tissue and/or vascular calcification. In this article, we consider movement of Ca with respect to the extracellular fluid (ECF) and develop a mathematical formulation for Ca homeostasis with respect to the ECF that includes input and output from the diet, the bone, the kidney, and dialysis. We consider calcium homeostasis in healthy individuals and in patients with excess parathyroid hormone, excess 1,25-dihydroxyvitamin D 3 , and metabolic acidosis; patients who have CKD and are not on dialysis; and, finally, patients who have CKD and are on dialysis. On the basis of a number of assumptions, dialysis patients with a daily intake of >37.5 mmol of elemental Ca (1.5 g) have movement of Ca into the ECF even without supplemental activated vitamin D. Addition of activated vitamin D, which increases intestinal Ca absorption and can increase resorption of Ca from bone, leads to the movement of Ca into the ECF at virtually all levels of intake; however, there are numerous unanswered questions regarding Ca homeostasis in patients with CKD, including how much of the Ca, administered as a phosphate binder, is absorbed and what is the fate of this absorbed Ca. Until these pressing questions are answered with well-designed experiments, we do not know whether we are doing more harm than good for our dialysis patients by administering additional Ca as a phosphate binder, especially when they also receive activated vitamin D.

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The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion.

Cited by 219 publications

References 25 publications

Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

20-Hydroxyvitamin D₂ is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells

Contribution of Intestine, Bone, Kidney, and Dialysis to Extracellular Fluid Calcium Content

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The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion.

Cited by 219 publications

References 25 publications

Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells

Contribution of Intestine, Bone, Kidney, and Dialysis to Extracellular Fluid Calcium Content

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20-Hydroxyvitamin D₂ is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells