Vitamins Metabolite analogues

Tretinoin (a//-frans-retinoic acid), a natural metabolite of vitamin A, was the first vitamin A analogue to be used orally, with some success, but its general therapeutic ratio did not differ markedly from that of vitamin A itself. 

Calcitriol is the main active metabolite of vitamin D, and synergizes with parathormone in mobilizing bone calcium and Increasing calcium absorption from the intestine. Vitamin D occurs in a number of sterol forms. These include vitamin D3 (cholecaldferol - the form in foods and made in the skin by the action of UV) vitamin Dj (ergocalciferol -also from plants). These forms are 25-hydroxylated in the kidney, and then la-hydroxylated in the kidney (under the control of parathormone), to make the most active form. This is available as calcitriol. Vitamin D facilitates the absorption of calcium and to a lesser extent, phosphorus, from the intestine and promotes deposition into the bones. A deficiency of vitamin D therefore results in bone deficiency disorders, e.g. rickets in children. Therapeutic replacement of vitamin D in cases of severe deficiency requires quantities of the vitamin best provided by one of the synthetic vitamin D analogues (e.g. alfacalcidol and dihydrotachysterol). 

Much attention hasbeen paid to the natural products becausethey have not only various biological activities but also are possible ligands for nuclear receptors, which are ligand-responsible transcription factors. Naturally occurring vitamin D analogues (vitamin D2, D3, D4, D5, D6 and D ) exhibit biological activities after converting to active metabolites, which act on a nuclear receptor, vitamin D receptor (VDR). 

Antagonistic metabolite analogues have been found for almost every known vitamin. For example, when the thiazole portion of thiamine (2.1) is replaced by a similarly substituted pyridine ring, the product ( pyrithia-mine ) produces characteristic symptoms of thiamine-deficiency in mice (Woolley, 1950) [see Section 9.4 for a commercially successful thiamine antagonist (9.24)]. 

Desoxypyridoxine [(9.3)3 R = --CH3] produces signs of vitamin deficiency in man, chicks, and rats, rapidly reversed by the vitamin [ (9.3)5 R = -CH20H] (Mueller and Vilter, 1950). For most of the vitamins, several antagonists are known. Metabolite analogues have also been found for aminoacids, purines, pyrimidines, some hormones, and the participating acids of the Krebs cycle. 

One of the major problems In the treatment of patients with vitamin D compounds (l.e., patients with hypoparathyroidism) has been the unpredictable development of hypercalcemia and the syndrome of vitamin D Intoxication. Although this problem may become less serious when some of the faster-acting metabolites and analogues of metabolites of vitamin D become available for clinical use. It Is likely that monitoring of serum levels of... 

Fluorinated analogues of the vitamin D3 metabolites have also been used as probes in NMR, to perform studies on the conformation of the complex between vitamin D and its receptor [160],... 

TREATMENT OF CALCIUM AND PHOSPHORUS DISORDERS WITH VITAMIN D3 METABOLITES AND ANALOGUES 34... 

It is now well established that l,25-(OH)2D3 is the active hormonal form of vitamin D3 [32], The production of l,25-(OH)2D3 in the kidney is regulated by dietary calcium and phosphate and also by changes in serum calcium and parathyroid hormone, which clearly highlight the hormonal nature of this compound. Functionally, the three classical actions of l,25-(OH)2D3 are to stimulate intestinal calcium and independently phosphate absorption, the mobilization of calcium from bone, and increase renal reabsorption of calcium. The focus of this review will be to explore the most recent concepts of vitamin D in regard to its metabolism and physiology, and with respect to the medicinal applications of vitamin D3 metabolites and analogues. 

Further evidence that C-25 and C-l hydroxylation are the activation steps of vitamin D3, and that C-24/C-23 and C-23/C-26-lactone metabolic conversions do not produce physiologically important products is with the use of side-chain fluoridated analogues of 25-OH-D3 [87, 88], Studies with these analogues were prompted by assertions that 24-hydroxylated or lactone metabolites are involved or required for such biological actions as mineralization of bone [89], suppression of parathyroid hormone secretion [90], cartilage metabolism [91], and embryonic development in the chick [92]. It is well established that plasma 24,25-(OH)2D3 concentrations (2-5 ng/ml) are approximately 50 times greater than those of l,25-(OH)2D3. Even so,... 

The metabolites of vitamin D are usually more toxic than the vitamin because the feedback mechanisms that regulate vitamin D concentrations are circumvented. 25-Hydroxycholecalciferol has a one-hundredfold increase in toxicity over vitamin when fed to chicks (220) and 1 a,25-dihydroxy vitamin is several times more toxic than the 25-hydroxy analogue. Vitamin D2 seems to have less toxicity than vitamin D, a circumstance which is believed to be caused by the mote efficient elimination of 25-hydtoxy and the 1 a,25-dihydtoxy vitamin D2 from the animals. Estimated safe upper dietary levels are given in Table 11. 

In the treatment of diseases where the metabolites are not being delivered to the system, synthetic metabolites or active analogues have been successfully administered. Vitamin D3 metabolites have been successfully used for treatment of milk fever in catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy in humans. Many of these clinical studies are outlined in References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamly of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated in the intestine, kidney, and bone, the metabolite acts on the immune system, p-cells of the pancreas (insulin secretion), cerebellum, and hypothalamus. 

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