1,25-Dihydroxy vitamin

In 1981, the lUPAC-IUB Joint Commission on Biochemical Nomenclature proposed that there be a set of trivial names for the important vitamin D compounds, including calciol [67-97-0] for vitaminD, calcidiol [19356-17-3] ion 25-hydroxy-vitaminD, and calcitriol [32222-06-3] ion 1 a,25-dihydroxy-vitamin D. This nomenclature has met with varying degrees of acceptance, as has the proposal to use calcine [69662-75-5] (deoxy-vitamin D2) and ercalcine [68323-40-0] (deoxy-vitamin D ) to name the triene hydrocarbon stmcture for 9,10-j (9-cholesta-5,7,10(19)-ttiene and... 

The yield of the fkst chemical synthesis of 1,25-dihydroxy-vitamin was <0.005% (124). A key kitermediate compound was 1,25-dihydroxy-cholesterol (109,125—130). 

The chemical syntheses of l,24(R),25-trihydroxy-vitamiQ [56142-94-0] and l,24(3),25-trihydroxy-vitamiQ D [56142-95-1] were reported (131,132) ki 1975. The chemical synthesis of 25,26-dihydroxy-vitamin [29261 -12-9] has also been described, and it has been determined that the biologically occurring epimer is 25(R),26-dihydroxy-vitamin (117,133—135). The 23,25-dihydroxy-24-oxo metabohte has been isolated (136) as well. 1 a-Hydroxycalcitroic acid (l-hydroxy-24-nor-9,10-secochola-5,7-10(19)-ttien-23-oic acid) [71204-89-2], 25-hydroxy-26,23-lactone vitamin [71203-34-6],... 

Vitamin D intoxication causes 25-hydroxy vitamin blood levels to go from a normal of 30—50 ng/mL to 200—400 ng/mL. At this high level, the metabohte can compete with 1 a-25-dihydroxy vitamin for receptors in the intestine and bone and induce effects usually attributed to the dihydroxy vitamin D. Thus, 25-hydroxy vitamin is beUeved to be the critical factor in vitamin D intoxication. Vitamin D2 is metabolized slower than vitamin and thus appears to be less toxic (218). 

The metabohtes 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 D when fed to chicks (220) and 1 a,25-dihydroxy vitamin D is several times more toxic than the 25-hydroxy analogue. Vitamin D2 seems to have less toxicity than vitamin D, a circumstance which is beheved to be caused by the more efficient elimination of 25-hydroxy and the 1 a,25-dihydroxy vitamin D2 from the animals. Estimated safe upper dietary levels are given in Table 11. 

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

A chiral nonracemic cyclic allyl iodide was shown to react with excess chromium(II) chloride and (4-methoxyphenylmethoxy)acetaldehyde to yield a single diastereomer, which was converted to la,25-dihydroxy vitamin D332. 

The steroid hormone 1,25-dihydroxy vitamin D3 (calcitriol) slowly increases both intestinal calcium absorption and bone resorption, and is also stimulated through low calcium levels. In contrast, calcitonin rapidly inhibits osteoclast activity and thus decreases serum calcium levels. Calcitonin is secreted by the clear cells of the thyroid and inhibits osteoclast activity by increasing the intracellular cyclic AMP content via binding to a specific cell surface receptor, thus causing a contraction of the resorbing cell membrane. The biological relevance of calcitonin in human calcium homeostasis is not well established. 

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... 

In addition to its classical role as regulator of calcium homeostasis, 1,25-dihydroxy vitamin D3 (calcitriol) displays immunosuppressive properties. Inhibition of T-lymphocyte proliferation seems to be mediated via regulation of CD80/86 costimulatory molecule expression on APCs. For clinical use as immunosuppressant, however, analogues of vitamin D3 that do not influence calcium metabolism are needed. 

Systemic regulators of osteoblast, osteocyte and osteoclast functions, and therefore of bone metabolism. The major bone-seeking hormones are parathyroid hormone (PIH), 1,25-dihydroxy vitamin D3 (calcitriol) and the various ex hormones. 

Summary term for a number of steroid hormones and their precursors with differentiation-inducing activity in many tissues. As regards bone, three components are relevant cholecalciferol ( vitamin D ) 25-hydroxyvi-taminD3 (calcidiol) and 1,25-dihydroxy vitamin D3 (calcitriol). The latter is the biologically active form and increases both intestinal calcium absoiption and bone resorption. Vitamin D preparations are widely used for the treatment of osteoporosis. Daily supplementation with vitamin D reduces bone loss in postmenopausal women and hip fractures in elderly subjects. 

Russell J et al Interaction between calcium and 1,25-dihydroxy-vitamin D3 in the regulation of preproparathyroid hormone and vitamin D receptor mRNA in avian parathyroids. Endocrinology 1993 132 2639. 

Lead has been shown to decrease circulating levels of the active form of vitamin D (1,25-dihydroxy-vitamin D) in children. The conversion of vitamin D to this active hormonal form 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 (heme-containing) system (Mahaffey et al. 1982 Rosen and Chesney 1983). Comparisons of the serum 1,25-dihydroxyvitamin D levels in children with blood lead levels of 33 g/dL with those in children with severe renal insufficiency (Rosen et al. 1980) and in children with an inborn error of vitamin D metabolism in which the 1-hydroxylase system or component... 

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). 

K. E., Fisher, J. M., Paine, M. F., Lown, K. S., Watkins, P. B., Expression of enzymatically active CYP3A4 in Caco-2 cells grown in extracellular matrix-coated permeable supports in the presence of 1-alpha,25-dihydroxy-vitamin D3, Mol. Pharmacol. 1997, 51, 741-754. 

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

TF transcription factor, R receptor, Fur ferric uptake regulation protein, NF-kB nuclear factor-kB, AP-1 activator protein-1, Egr-1 early growth response-1, VDR la,25-dihydroxy-vitamin D3 receptor, RXR retinoid X receptor, PPARy peroxisome proliferator-activated receptor y NFAT nuclear factor of activated T-cells, HSF heat shock factor, p53 tumor suppressor p53, HIF-1 hypoxia inducible factor-1. ... 

OH)2 D3 or dihydroxy vitamin D3) occurs in mitochondria of the proximal tubules. The pathway of dihydroxy vitamin D3 synthesis is shown in Figure 8.11. 

Figure 8.12 Feedback control of dihydroxy vitamin D3 synthesis by ionized calcium...

Calcium is the major mineral component of bone and normal repair and remodelling of bone is reliant on an adequate supply of this mineral. Calcium uptake in the gut, loss through the kidneys and turnover within the body are controlled by hormones, notably PTH and 1,25 dihydroxy cholecalciferol (1,25 DHCC or 1,25 dihydroxy vitamin D3 or calcitriol). Refer to Figure 8.12 for a summary of the involvement of PTH and vitamin D3 in controlling plasma calcium concentration. These two major hormones have complementary actions to raise plasma calcium concentration by promoting uptake in the gut, reabsorption in the nephron and bone resorption. Other hormones such as thyroxine, sex steroids and glucocorticoids (e.g. cortisol) influence the distribution of calcium. 

There seems to be no metabolic control exerted on hepatic 25-hydroxylase and so all of the available cholecalciferol is converted. Hydroxylation in the kidney however is an important control point being regulated by PTH, and indirectly therefore by calcium and phosphate concentrations. Stimulation of la-hydroxylase by PTH is via a cyclic AMP (cAMP) -dependent mechanism and longer-term regulation of the activity of this enzyme is via induction mediated by other hormones such as oestrogens, cortisol and growth hormone. Typically, the plasma concentration of 1,25 dihydroxy vitamin D is in the range 20-60 ng/1, that is approximately 1000-times lower than that of its precursor. 

When 1,25 DHCC provision is adequate or when plasma calcium concentration is above approximately 2.20mmol/l, la hydroxylase activity is suppressed and 25-hydroxy vitamin D3 is converted by 24-hydroxylase into 24,25 dihydroxy vitamin D3 a metabolite whose true role is uncertain but one which seems to have little if any physiological activity. Renal 24-hydroxylase does have a role to play in the deactivation of 1,25 dihydroxy vitamin D the major metabolite of the vitamin being 1,24,25 trihydroxy vitamin D. 

Thummel KE, Brimer C, Yasuda K, Thottassery J, Senn T, Lin Y, Ishizuka H, Kharasch E, Schuetz J, Schuetz E (2001) Transcriptional control of intestinal cytochrome P-4503A by 1-alpha, 25-dihydroxy vitamin D3. Mol Pharmacol 60 1399-1406. 

Rehan VK, Torday JS, Peleg S, Gennaro L, Vouros P, Padbury J, Rao DS, Reddy GS (2002) lAlpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1 alpha,25-dihydroxy vitamin D3 production and biological activity studies in pulmonary alveolar type II cells. Mol Genet Metab 76(l) 46-56... 

Kleuser, B., Cuvillier, O. and Spiegel, S., 1998, la,25-Dihydroxy vitamin Dsinhibits... 

---