Hydroxyvitamin D3 and la,25-Dihydroxyvitamin

Both la-hydroxyvitamin D3 and la,25-dihydroxyvitamin D3 increase bone formation and bone resorption in vitro and in the rachitic animal 100,153,183,188,197). 

The advances in our understanding of vitamin D3 metabolism which have been described in the previous sections have promoted the rapid use of some of these compounds in the clinic. Both la-hydroxyvitamin D3 and la,25-dihydroxyvitamin D3 have been studied in several disease states, such as chronic renal failure 28, 32, 33, 51, 71, 115, 144), hypoparathyroidism 74, 159), osteomalacia 23, 87), osteoporosis 106), and neonatal hypocalcemia 47,96). 

The Biological Activities of Pure Crystalline la-Hydroxyvitamin D3 and la,25-Dihydroxyvitamin D3. Mol. Cell Endo. 1, 305 (1974). 

A 40-year-old man with chronic kidney disease on phenytoin for seizme prophylaxis after an intracranial hemorrhage developed severe hypocalcemia associated with profound vitamin D deficiency. Phenytoin affects the cytochrome P450 system and can accelerate the breakdown of 25-hydroxyvitamin D3 and la,25-dihydroxyvitamin D3. Therefore, patients with chronic kidney disease may be more likely to develop hypocalcemia on phenytoin due to its effects on vitamin D metabolism [135 ]. 

Both the synthetic analog, la-hydroxyvitamin D3 (7), and la,25-hydroxyvitamin D3 are potent stimulators of intestinal calcium absorption in organ culture 37, 58) in rats and chickens 26,36,69,145,146,198) fed vitamin D3 and calcium deficient diets. The ratio of activities of la-hydroxy- and la,25-dihydroxyvitamin D3 compared to the activity of vitamin D3 itself reaches 1000 in parathyroidectomixed-thyroidectomized animals 146). However, what these ratios mean as regards the therapeutic value of la-hydroxyvitamin D3 or la,25-dihydroxyvitamin D3 is not easy to assess. In clinical situations of impaired calcium utilization, there normally would be an adequate supply of calcium, phosphorous, and vitamin D3 in the diet. However, in certain metabolic dysfunctions (see Section 6) both la- and la,25-dihydroxyvitamin D3 have been clearly demonstrated to have therapeutic value. 

Bareis, P., E. Kallay, M.G. Bischof, G. Bises, H. Hofer, C. Potzi et al. (2002). Clonal differences in expression of 25-hydroxyvitamin Dj-la-hydroxylase, of 25-hydroxyvitamin Dj-24-hydroxylase, and of the vitamin D receptor in human colon carcinoma cells Effects of epidermal growth factor and la,25-dihydroxyvitamin D3. Exp. Cell Res. 276, 320-327. 

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... 

Fritsche, J. et al. (2003) Regulation of 25-hydroxyvitamin D3 - la-hydroxylase and production of la,25-dihydroxyvitamin D3 by human dendritic cells. Blood, 102, 3314-3316. 

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

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. 

The active form of vitamin D3, la,25-dihydroxy-vitamin D3, is an important regulator of calcium metabolism and elicits most of its biological effects by binding to a high-affmity receptor in target tissues. In the formation of la,25-dihydroxyvitamin D3, vitamin D3 is hydroxylated in two sequential steps. An initial 25-hydroxylation in the liver is followed by an la-hydroxylation in the kidney (De-Luca and ScHNOES 1983). The 25-hydroxyvitamin D3 la-hydroxylase (la-hydroxylase) is the key enzyme in the determination of the level of la,25-dihydroxyvitamin D3 and plays a vital role in calcium homeostasis. It is present in the inner mitochondrial membrane of renal proximal tubular cells (Kawashima et al. 1981, Paulson and DeLuca 1985). While under physiological conditions, the kidney is the only site of la,25-dihydroxyvitamin D3 (DeLuca 1988), in sarcoidosis or lymphoma, la-hydroxylase may be expressed at other sites (Armbrecht et al. 1992). 

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. 

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