D and its Metabolites

25(OH)2D3 inhibited proliferation and induced differentiation and apoptosis in human colon, breast, prostate and gynecological cancers as well as several forms of hematopoietic cancer (Studzinski and Moore, 1995 van Leeuwen and Pols, 1997). Experimental animal studies show that 1, 25(OH)2D3 inhibited chemically-induced breast, colon, and skin tumors. The growth of colon, breast and prostate cancer cells, as well as melanoma and retinoblastoma cells implanted into rodents was retarded by treatment with 1, 25(OH)2D3 (Studzinski and Moore, 1995 van den Bemd et al, 2000). 

Epidemiologic evidence suggests that low exposure to sunlight, low dietary intake of vitamin D and low plasma levels of 25(OH)D3 and 1, 25(OH)2D3 increase the risk of developing colon, breast and prostate cancer (Studzinski and Moore, 1995 van den Bemd et al., 2000 Zittermann, 2003). There is evidence that vitamin D deficiency can attenuate the beneficial effect of dietary calcium for the prevention of colonic adenoma and carcinoma (Parodi, 2001a). 

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Utility. Insufficient data Is available on the measurement of 1,25(0H)2D3 for evaluation of Its utility In clinical medicine. A major breakthrough In methodology will be needed before routine application will be possible. This could come with the development of a battery of radioimmunoassays for the measurement of all of the vitamin D metabolites. So far, however, the development of antibodies to vitamin D and Its metabolites has been limited by apparently Irreversable changes In the Important B ring of the sterol which occur during Its conjugation to Immunogenic proteins. 

It has also been demonstrated in animals that lead blocks the intestinal responses to vitamin D and its metabolites (Smith et al. 1981). Dietary concentrations of lead in combination with a low phosphorus or a low calcium diet administered to rats suppressed plasma levels of the vitamin D metabolite, 1,25-dihydroxycholecaliferol, while dietary intakes rich in calcium and phosphorus protected against this effect (Smith et al. 1981). Thus, animals fed a diet high in calcium or phosphorus appear to be less susceptible to the effects of lead, because of hindered tissue accumulation of lead. 

Smith CM, Deluca HF, Tanaka Y, et al. 1981. Effect of lead ingestion on functions of vitamin D and its metabolites. JNutr 111 1321-1329. 

Vitamin D and its metabolites are bound in plasma to a carrier protein. These molecules are cleared by the liver, 25-hydroxyvitamin D and... 

Vitamin D and its metabolites circulate in plasma tightly bound to a carrier protein, the vitamin D-binding protein. This .-globulin binds 25(OH)D and 24,25(OH)2D with comparable high affinity and vitamin D and l,25(OH)2D with lower affinity. 

As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels. 

Vitamin D and its metabolites circulate in plasma tightly bound to a carrier protein, the vitamin D-binding protein. This -globulin binds 25(OH)D and 24,25(OH)2D with comparable high affinity and vitamin D and l,25(OH)2D with lower affinity. In normal subjects, the terminal half-life of injected calcifediol is 23 days, whereas in anephric subjects it is 42 days. The half-life of 24,25(OH)2D is probably similar. Tracer studies with vitamin D have shown a rapid clearance from the blood. The liver appears to be the principal organ for clearance. Excess vitamin D is stored in adipose tissue. The metabolic clearance of calcitriol in humans indicates a rapid turnover, with a... 

In mild forms of malabsorption, vitamin D (25,000-50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, since no impairment of the renal metabolism of 25(OH)D to l,25(OH)2D and 24,25(OH)2D exists in these patients. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels. 

Since sunlight seems to play an important role in preventing the development of prostate cancer (H4), it leads to the investigation of vitamin D and its metabolites as anticancer agents in prostatic cell cultures and the Dunning rat model. Treatment of prostatic cell lines PC-3 and LNCaP in vitro and in the Dunning rat model with the 1,25-D metabolite causes a decrease in proliferation of tumor cells (F7, G9,... 

HolickMF (1990) The use and interpretation of assays for vitamin D and its metabolites. Journal of Nutrition 120(Suppl 11), 1464-9. 

The Homer-Wittig process has been utilized in the synthesis of vitamin D and its metabolites. Recently, a process was developed for the synthesis of hydrindanols by the 1,4-addition of the phosphine oxide to cyclopentenone. After further elaboration, the phosphine oxide formed (250) can be utilized to incorporate side chains (251 equation 58). 

The differences in their polarities, because of the number of hydroxyl groups, have been used to separate vitamin D and its metabolites. With three hydroxyl groups, l,25(OH)2D is more polar than 25(OH)D, with two hydroxyls, which is more polar than vitamin D, with one hydroxyl group. 

Adams JS, Clemens TL, Holick MR Silica Sep-Pak preparative chromatography of vitamin D and its metabolites. J Chromatogr 1981 226 198-201. 

Horst RL, Littledike ET, Riley JL, Napoli JL. Quantitation of vitamin D and its metabolites and their plasma concentration in five species of animals. Anal Biochem 1981 116 189-203. 

Seamark DA, Trafford DJH, Makin HLJ. The estimation of vitamin D and its metabolites in human plasma. J Steroid Biochem 1981 14 111-23. 

Four primary factors influencing calcium and phosphate homeostasis are diet, vitamin D and its metabolites, PTH, and calcitonin. Table 37-1 lists other hormones known to... 

Thus, a complex relationship exists among serum Ca + and phosphate, PTH, and vitamin D and its metabolites. Release of PTH in response to low serum Ca + directly mobilizes calcium from bone and increases synthesis of 1, 25-(0H)2D, which in turn mobilizes skeletal Ca + and causes increased intestinal calcium absorption. These effects raise the serum Ca level sufficiently to reduce PTH secretion. The effect of PTH on the kidneys occurs within minutes, whereas the effects of PTH on bone and (indirectly) on intestine take hours and days, respectively. An increase in serum phosphate acts in a way qualitatively similar to that of hypocalcemia to release PTH, increase excretion of phosphate in the proximal tubules, and decrease intestinal phosphate absorption. These events are mediated predominantly by the decrease in serum calcium that accompanies a rise in phosphate concentration. In addition, phosphate may inhibit 25-(OH)D-la-hydroxylase. 

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