24 ,25-Dihydroxyvitamin

The appearance and role of intestinal CaBP will not be further discussed here except to say that originally its appearance was thought to coincide exactly (48, 50) with the appearance and rise of Ca concentration in the serum of rachitic animals. However, this is now open to question, as its appearance has now been shown to be delayed up to 2 hours after the rise of Ca begins (63, 100, 177, 191). 

It was Boyle (25) in 1971 who first demonstrated that under normal or hypercalcemic conditions a major circulating metabolite of 25-hydroxyvitamin D3 is 24,25-dihydroxyvitamin D3 (5). He claimed in 1973 (27) that 24,25-dihydroxyvitamin D3 is capable of inducing intestinal calcium transport at dose levels similar to that of la,25-dihydroxyvitamin D3 but has little ability to cause bone resorption and further showed that 24,25-dihydroxyvitamin D3 was metabolized to a more potent metabolite in the kidney before these activities were observed. DeLuca (76) in 1973 showed that in chickens this more potent metabolite was la,24,25-trihydroxy-vitamin D3 (6), although the configuration at the 24-position was not defined at this time, and that in chickens (6) was only 60 percent as active as vitamin D3 in curing rickets and was less active than la,25-dihydroxy-vitamin D3 in stimulating and sustaining intestinal calcium transport and bone resorption. He further indicated that this mixime of 24-isomers had preferential action on the intestine and did not cause bone resorption as much as was expected. More recently, Uskokovic (143) has chemically 

Some conflicting statements have been made concerning the relative potencies of compounds possessing of the 24 R)- and 24(iS)-configuration in the vitamin D3 side chains. DeLuca (185) claims that both synthetically derived 24-hydroxyvitamin D3 isomers stimulate intestinal calcium transport almost equally well in the rat and has shown that the 24(S)-isomer has little or no activity in bone calcium resorption or in bone formation, whereas the 24(/ )-isomer is almost as active as 25-hydroxyvitamin D3 in these in vivo tests. However, Atkins (7) claims that both diastereo-isomers of 24,25-dihydroxyvitamin D3 are potent stimulators of bone resorption in tissue culture and there is no significant difference between the (R)- and (5)-forms. Boris (24) recently also showed that both 24 R)-and 24(/S)-isomers of la,24,25-trihydroxyvitamin D3 promote bone mineralization almost equally well in cockerels. Whether the differentiation of the 24(i )- and 24(5)-diastereoisomers in bone formation and resorption occurs only in the absence of the la- and the 25-hydroxy substituents is not known at this time, but it seems unlikely. 

Norman (152) in 1977 reported that la,24(i ),25-trihydroxyvitamin D3 is less potent than la,25-dihydroxyvitamin D3 in the rachitic chick in terms of its ability to stimulate intestinal calcium absorption, mobilize bone calcium, and induce intestinal calcium binding protein. DeLuca (27) had shown earlier that 24,25-dihydroxyvitamin D3 must be converted to la,24,25-trihydroxyvitamin D3 in the kidney in order to have biological activity. Gray (62) in 1974 had demonstrated presence of a peak in the analysis of the plasma of normal and nephrectomized humans given H-labeled 25-hydroxyvitamin D3, which was chromatographically similar to authentic la,24,25-trihydroxyvitamin D3. DeLuca 182) has recently shown that the renal 24-hydroxylase enzyme requires presence of a hydroxyl group be on the 25-carbon of the vitamin D3 molecule before further hydroxylation can take place. The 24(i )-hydroxylase is, however, not totally isolated in the kidney as the la-hydroxylase appears to be. DeLuca 182) finds that nephrectomized animals also metabolize la,25-dihydroxyvitamin D3 to la,24(i ),25-trihydroxyvitamin D3. 

As can be seen from the above work, the role of la,24(/ ),25-tri-hydroxyvitamin D3 is becoming more ubiquitous. Originally, synthesis of this metabolite was thought to be a mechanism employed by the body for ridding itself of circulating levels of la,25-dihydroxyvitamin D3 after the successful attainment of the normal concentration of calcium in the serum (see Fig. 3). It now seems, however, that this trihydroxy metabolite of vitamin D3 is becoming more influential in the overall conservation of calcium homeostasis. 

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Dihydroxyvitamin (283) is the endogenous ligand for the vitamin receptor (VDR). It modulates genomic function in a tissue and developmentaHy specific manner and affects ceU proliferation, differentiation, and mineral homeostasis (74). Vitamin mobilizes calcium from the bone to maintain plasma Ca " levels. Vitamin and VDR are present in the CNS where they may play a role in regulating Ca " homeostasis. Vitamin D has potent immunomodulatory activity in vivo. 

FIGURE 18.37 (a) Vitamin D3 (cholecalciferol) is produced in the skin by the action of sunlight on 7-dehydrocholesterol. The successive action of mixed-function oxidases in the liver and kidney produces 1,25-dihydroxyvitamin D3, the active form of vitamin D. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

LiEL Y, SHANY s, SMIRNOFF p and SCHWARTZ B (1999) Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinol 140, 280-85. 

Amir, H. et ah. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells, Nutr. Cancer, 33, 105, 1999. 

Diet Increased risk associated with high-meat and high-fat diets. Decreased intake of 1, 25-dihydroxyvitamin D, vitamin E, lycopene, and /Tcarotene increases risk. 

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

A third and less common mechanism is production of 1,25-dihydroxyvitamin D by tumor cells (usually lymphoma), which increases GI absorption of calcium and enhances osteoclastic bone resorption. 

NS (general population) Other Negative correlation between blood lead and serum 1,25-dihydroxyvitamin D in children 12-120 Mahaffey et al. 1982 Rosen et al. 1980... 

Effects on Vitamin D Metabolism. Lead interferes with the conversion of vitamin D to its hormonal form, 1,25-dihydroxyvitamin D. This conversion takes place via hydroxylation to 25-hydroxyvitamin D in the liver followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome P-450 system (Mahaffey et al. 1982 Rosen and Chesney 1983). Evidence for this effect comes primarily from studies of children with high lead exposure. 

The possible mechanism kidney-induced hypertension is discussed in Section 2.4.2, Mechanisms of Toxicity. Lead appears to affect vitamin D metabolism in renal tubule cells, such that circulating levels of the vitamin D hormone, 1,25-dihydroxyvitamin D, are reduced. This effect is discussed later in this section under Other Systemic Effects. 

Reduction in the serum 1,25-dihydroxyvitamin D concentration has been reported as an indicator of increased lead absorption or lead levels in the blood (Rosen et al. 1980). Lead inhibits the formation of this active metabolite of vitamin D, which occurs in bone mineral metabolism (EPA 1986a Landrigan 1989). Children with PbB concentrations of 12-120 pg/dL lead showed decreased serum 1,25-dihydroxyvitamin D concentrations comparable to those found in patients with hypoparathyroidism, uremia, and metabolic bone disease (Mahaffey et al. 1982 Rosen et al. 1980). This biomarker is clearly not specific for lead exposure and several diseases can influence this measurement. 

Children with elevated PbB (12-120 pg/dL) were found to have significantly lower serum concentrations of the vitamin D metabolite 1,25-dihydroxy vitamin D compared with age-matched controls (p<0.001), and showed a negative correlation of serum 1,25-dihydroxyvitamin D with lead over the range of blood lead levels measured (Mahaffey et al. 1982 Rosen et al. 1980). 

Long GJ, Rosen JF. 1994. Lead perturbs 1,25 dihydroxyvitamin D3 modulation of intracellular calcium metabolism in clonal rat osteoblastic (ros 17/2.8) cells. Life Sci 54(19) 1395-1402. 

Rosen JF, Chesney RW, Hamstra AJ, et al. 1981. Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption. In Brown SS, Davis DS, eds. Organ-directed toxicity Chemical indices and mechanisms. New York, NY Pergamon Press, 91-95. 

Vitamin D receptor (VDR) 1,25 dihydroxyvitamin-D3 Vitamin D response in patients affected with rickets (96) Susceptibility to osteoporosis (97) and autosomal dominant rickets disease (96)... 

L The answer is e. (Kalzang, pp 744, 748J Vitamin is hydroxylated to 2.5-0ITDj (calcifediol). Calcifediol is then hydroxylated in the kidney to the most active form of vitamin D, which is 1,25-dihydroxyvitamin D (cal-citriol). Calcitriol has a rapid onset of action and a short half-life. The administration of calcitriol causes the elevation of serum Ca levels by enhancing the intestinal absorption of Ca. Calcitriol is indicated in vitamin D deficiency,... 

Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses PTH synthesis and secretion and upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. The dose depends on the stage of CKD and type of dialysis (Table 76-4). 

There has been some concern expressed regarding the use of CSFs to treat MDS patients. Because these cytokines have proliferative activity, they have the potential to induce a leukaemic transformation in the malignant clone. However, the combined use of CSFs with cytotoxic drugs such as cytosine arabinoside (ara-C) appears promising. If leukaemic clones are induced to proliferate by the cytokine, then they are killed by ara-C as they enter the cell cycle. Other forms of differentiation therapy, such as treatment with retinoids, 1,25-dihydroxyvitamin D3 and interferons, have also been tested, but results have been variable. 

Danan JL, Delorme AC, Mathieu H. 1982. Presence of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 24-hydroxylase in vitamin D target cells of rat yolk sac. J Biol Chem 257 10715-10721. 

Milde, P., Merke, J., Ritz, E., Haussler, M., and Rauterberg, E. (1989) Immuno-histochemical detection of 1,25-dihydroxyvitamin D3 receptors and estrogen receptors by monoclonal antibodies comparison of four immunoperoxidase methods. J. Histochem. Cytochem. 37,1609-1617. 

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