Calcium Absorption and the Molecular Effects OF Vitamin D3

Background: Vitamin D and calcium are important dietary compounds that affect bone mass, even if other minerals (potassium, zinc, etc.) and vitamins (A, C and K) are also involved. Vitamin D and certain minerals, in fact, play an important role in calcium homeostasis and calcium absorption. Hip fracture incidence is higher in Europe and the United States, where calcium is frequently included in the human diet; while the occurrence of these fractures is lower in developing countries, where diets are often poor in calcium. This condition is named the “calcium paradox”, and may be partially explained by phosphate toxicity, which can negatively affect mineral metabolism. It is important to maintain correct dietary calcium-phosphate balance in order to have a healthy life, reducing the risk of osteoporotic fractures in older people. Vitamin D can also act as a hormone; vitamin D2 (ergocalciferol) is derived from the UV-B radiation of ergosterol, the natural vitamin D precursor detected in plants, fungi, and invertebrates. Vitamin D3 (cholecalciferol) is synthesized by sunlight exposure from 7-dehydrocholesterol, a precursor of cholesterol that can also act as provitamin D3. Dietary intake of vitamin D3 is essential when the skin is exposed for short periods to ultraviolet B light (UV-B), a category of invisible light rays such as UV-A and UV-C. This can be considered the usual situation in northern latitudes during the winter season, or the typical lifestyle for older people and/or for people with very white delicate skin. The actual recommended daily intake of dietary vitamin D is strictly correlated with age, ranging from 5 μg for infants, children, teenagers, and adults—including pregnant and lactating women—to 15 μg for people over 65 years.

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Calcium absorption and intestinal calcium-binding protein: quantitative relationship.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1979.236.5.e556 ◽

1979 ◽

Vol 236 (5) ◽

pp. E556 ◽

Cited By ~ 1

Author(s):

J J Feher ◽

R H Wasserman

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Calcium Binding ◽

Calcium Absorption ◽

Binding Protein ◽

Quantitative Relationship ◽

Calcium Binding Protein ◽

Vitamin D Status ◽

Loop Technique

The concentration of the vitamin D-induced calcium-binding protein (CaBP) and calcium absorption from the duodenum were investigated in chicks with an in vivo ligated-loop technique. The relation between CaBP and calcium absorption was dependent on a) source of vitamin D activity (either vitamin D3 or 1,25-dihydroxycholecalciferol); b) dosage of vitamin D3; c) time after administration of vitamin D3 to rachitic animals. To aid in the interpretation of these results, a phenomenological model was developed in which CaBP was viewed as being linearly related to a portion of calcium absorption. The model, when applied to the data, suggests that there is a "nonfunctional" pool of CaBP the size of which is determined by the vitamin D status of the animal. After correction for this nonfunctional pool, the proportionality between CaBP and calcium absorption is independent of the vitamin D status of the animal.

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Novel vitamin D analogs that modulate leukemic cell growth and differentiation with little effect on either intestinal calcium absorption or bone mobilization

Blood ◽

10.1182/blood.v74.1.82.82 ◽

1989 ◽

Vol 74 (1) ◽

pp. 82-93 ◽

Cited By ~ 103

Author(s):

JY Zhou ◽

AW Norman ◽

M Lubbert ◽

ED Collins ◽

MR Uskokovic ◽

...

Keyword(s):

Vitamin D ◽

Mechanism Of Action ◽

Vitamin D3 ◽

Clonal Growth ◽

Calcium Absorption ◽

Active Form ◽

Intestinal Calcium Absorption ◽

Leukemic Cells ◽

Binding Studies ◽

Vitamin D Analogs

Abstract Induction of terminal differentiation of leukemic and preleukemic cells is a therapeutic approach to leukemia and preleukemia. The 1 alpha, 25- dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D3, can induce differentiation and inhibit proliferation of leukemia cells, but concentrations required to achieve these effects cause life-threatening hypercalcemia. Seven new analogs of 1,25(OH)2D3 were discovered to be either equivalent or more potent than 1,25(OH)2D3 as assessed by: (a) inhibition of clonal proliferation of HL-60, EM-2, U937, and patients' myeloid leukemic cells: and (b) induction of differentiation of HL-60 promyelocytes. Furthermore, these analogs stimulated clonal growth of normal human myeloid stem cells. The most potent analog, 1,25-dihydroxy-16ene-23yne-vitamin D3, was about fourfold more potent than 1,25(OH)2D3. This analog decreased clonal growth and expression of c-myc oncogene in HL-60 cells by 50% within ten hours of exposure. Effects on calcium metabolism of these novel analogs in vivo was assessed by intestinal calcium absorption (ICA) and bone calcium mobilization (BCM). Each of the analogs mediated markedly less (10 to 200-fold) ICA and BCM as compared with 1,25(OH)2D3. To gain insight into the possible mechanism of action of these new analogs, receptor binding studies were done with 1,25(OH)2–16ene-23yne-D3 and showed that it competed only about 60% as effectively as 1,25(OH)2D3 for 1,25(OH)2D3 receptors present in HL-60 cells and 98% as effective as 1,25(OH)2D3 for receptors present in chick intestinal cells. In summary, we have discovered seven novel vitamin D analogs that are more potent than the physiologic 1,25(OH)2D3 as measured by a variety of hematopoietic assays. In contrast, these compounds appear to have the potential to be markedly less toxic (induction of hypercalcemia). These novel vitamin D compounds may be superior to 1,25(OH)2D3 in a number of clinical situations including leukemia/preleukemia; they will provide a tool to dissect the mechanism of action of vitamin D seco-steroids in promoting cellular differentiation.

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Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism

Blood ◽

10.1182/blood.v78.1.75.bloodjournal78175 ◽

1991 ◽

Vol 78 (1) ◽

pp. 75-82 ◽

Cited By ~ 1

Author(s):

JY Zhou ◽

AW Norman ◽

M Akashi ◽

DL Chen ◽

MR Uskokovic ◽

...

Keyword(s):

Vitamin D3 ◽

Calcium Metabolism ◽

Calcium Absorption ◽

Leukemic Cells ◽

Inhibition Of Proliferation ◽

Myc Oncogene ◽

Differentiation And Proliferation ◽

Bone Abnormalities

We describe several novel analogs of the seco-steroid 1,25(OH)2-vitamin D3[1,25(OH)2D3] and their effects on differentiation and proliferation of HL-60 human myeloid leukemic cells in vitro as well as their effects on calcium metabolism in vivo. The 1 alpha-25(OH)2–16ene-23yne-26,27F6- vitamin D3 is the most potent analog reported to date, having about 80- fold more activity than the reference 1,25(OH)2D3 for inhibition of proliferation and induction of differentiation of HL-60 cells. Also, this analog decreased RNA expression of MYC oncogene in HL-60 by 90% at 5 x 10(-10) mol/L. Intriguingly, intestinal calcium absorption and bone calcium mobilization mediated in vivo by 1 alpha-25(OH)2–16ene-23yne- 26,27F6-D3 was found to be markedly (15-fold) less than that of 1,25(OH)2D3. In addition, 1 alpha-25(OH)2D3 bound to 1,25(OH)2D3 receptors of both HL-60 and intestine more avidly than did 1 alpha- 25(OH)2–16ene-23yne-26,27F6-D3. This novel analog may open up new therapeutic strategies for several hematopoietic, skin, and bone abnormalities and may provide a new tool to understand how vitamin D3 seco-steroids induce cellular differentiation.

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Vitamin D3 and Calcium Absorption

Clinical Science ◽

10.1042/cs0630329 ◽

1982 ◽

Vol 63 (3) ◽

pp. 329-329

Author(s):

J. Reeve

Keyword(s):

Vitamin D3 ◽

Calcium Absorption

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Calcium absorption and the vitamin D3-dependent calcium-binding protein

Calcified Tissue Research ◽

10.1007/bf02062596 ◽

1971 ◽

Vol 7 (1) ◽

pp. 81-92 ◽

Cited By ~ 32

Author(s):

R. A. Corradino ◽

J. G. Ebel ◽

P. H. Craig ◽

A. N. Taylor ◽

R. H. Wasserman

Keyword(s):

Vitamin D3 ◽

Calcium Binding ◽

Calcium Absorption ◽

Binding Protein ◽

Calcium Binding Protein

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Novel vitamin D analogs that modulate leukemic cell growth and differentiation with little effect on either intestinal calcium absorption or bone mobilization

Blood ◽

10.1182/blood.v74.1.82.bloodjournal74182 ◽

1989 ◽

Vol 74 (1) ◽

pp. 82-93 ◽

Cited By ~ 1

Author(s):

JY Zhou ◽

AW Norman ◽

M Lubbert ◽

ED Collins ◽

MR Uskokovic ◽

...

Keyword(s):

Vitamin D ◽

Mechanism Of Action ◽

Vitamin D3 ◽

Clonal Growth ◽

Calcium Absorption ◽

Active Form ◽

Intestinal Calcium Absorption ◽

Leukemic Cells ◽

Binding Studies ◽

Vitamin D Analogs

Induction of terminal differentiation of leukemic and preleukemic cells is a therapeutic approach to leukemia and preleukemia. The 1 alpha, 25- dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D3, can induce differentiation and inhibit proliferation of leukemia cells, but concentrations required to achieve these effects cause life-threatening hypercalcemia. Seven new analogs of 1,25(OH)2D3 were discovered to be either equivalent or more potent than 1,25(OH)2D3 as assessed by: (a) inhibition of clonal proliferation of HL-60, EM-2, U937, and patients' myeloid leukemic cells: and (b) induction of differentiation of HL-60 promyelocytes. Furthermore, these analogs stimulated clonal growth of normal human myeloid stem cells. The most potent analog, 1,25-dihydroxy-16ene-23yne-vitamin D3, was about fourfold more potent than 1,25(OH)2D3. This analog decreased clonal growth and expression of c-myc oncogene in HL-60 cells by 50% within ten hours of exposure. Effects on calcium metabolism of these novel analogs in vivo was assessed by intestinal calcium absorption (ICA) and bone calcium mobilization (BCM). Each of the analogs mediated markedly less (10 to 200-fold) ICA and BCM as compared with 1,25(OH)2D3. To gain insight into the possible mechanism of action of these new analogs, receptor binding studies were done with 1,25(OH)2–16ene-23yne-D3 and showed that it competed only about 60% as effectively as 1,25(OH)2D3 for 1,25(OH)2D3 receptors present in HL-60 cells and 98% as effective as 1,25(OH)2D3 for receptors present in chick intestinal cells. In summary, we have discovered seven novel vitamin D analogs that are more potent than the physiologic 1,25(OH)2D3 as measured by a variety of hematopoietic assays. In contrast, these compounds appear to have the potential to be markedly less toxic (induction of hypercalcemia). These novel vitamin D compounds may be superior to 1,25(OH)2D3 in a number of clinical situations including leukemia/preleukemia; they will provide a tool to dissect the mechanism of action of vitamin D seco-steroids in promoting cellular differentiation.

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