Of la-hydroxyvitamin

Whereas the intermolecular Heck reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and many cyclic compounds can be prepared by the intramolecular Heck reaction [37]. The stereospecific synthesis of an A ring synthon of la-hydroxyvitamin D has been carried out. Cyclization of the (7T)-alkene 88 gives the (fT)-exo-diene 90, and the (Z)-alkene 91 affords the (Z)-exo-diene 92 [38]. These reactions are stereospecific, and can be understood by cis carbopalladation to form 89 and the. sun-elimination mechanism. 

Tabata, T. et al. (1986) The effect of la-hydroxyvitamin D3 on cell-mediated immunity in hemodialyzed patients. The Journal of Clinical Endocrinology and Metabolism, 63, 1218-1221. 

Morimoto, S. et al. (1986) Treatment of psoriasis vulgaris by oral administration of la-hydroxyvitamin D3 - open-design study. Calcified Tissue International, 39, 209-212. 

Saarem K, Pedersen J1 (1985) 25-hydroxylation of la-hydroxyvitamin Dj in rat and human liver. 

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. 

In osteomalacia associated with malabsorption problems and nutritional osteomalacia, small doses of la-hydroxyvitamin D3 and la,25-di-hydroxyvitamin D3 are efficacious. Clinical response is impressive even during the first week with doses as low as 0.25 pg daily. 

Harmeyer, J., and H. F. DeLuca Calcium Binding Protein and Calcium Absorption after Vitamin D Administration. Arch. Biochem. Biophys. 133, 247 (1969). Harrison, I. T., and B. Lythgoe Calciferol and its Relatives. Part III. Partial Synthesis of Calciferol and of Epicalciferol. J. Chem. Soc. (London) 1958, 837. Harrison, R. G., B. Lythgoe, and P. W. Wright Calciferol and its Relatives. Part XVIII. Total Synthesis of la-Hydroxyvitamin D3. J. Chem. Soc. Perkin I 1974, 2654. 

In a further study, serum concentrations of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D and la,25-dihydroxyvitamin D were measured in 10 Cd-exposed subjects and 5 non-exposed subjects [100]. The Cd-exposed subjects were divided into two groups according to serum la,25-dihydroxyvitamin D levels. No significant differences for 25-hydroxyvitamin D were found between the Cd-exposed group with low or normal serum la,25-dihydroxyvitamin D and the... 

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. 

Morimoto, S. and Kumahara, Y. (1985) A patient with psoriasis cured by la-hydroxyvitamin D3. Medical Journal of Osaka University, 35, 51-54. 

Conclusive evidence that a species of cytochrome P-450 was involved in the hydroxylation was presented by Okuda et al., who showed that the photochemical action spectrum for reversal of the carbon monoxide inhibition of 26-hydroxylation of 5)8-cholestane-3a,7a,12a-triol in rat liver exhibited a maximum at 450 nm [134]. Pedersen et al. [135] and Sato et al. [136] reported simultaneously that small amounts of cytochrome P-450 could be solubilized from the inner membranes of rat liver mitochondria that was active towards cholesterol as well as 5)8-cholestane-3a,7a,12a-triol in the presence of ferredoxin, ferredoxin reductase and NADPH. The mechanism of hydroxylation is thus the same as that operative in the biosynthesis of steroid hormones in the adrenals and in the la-hydroxylation of 25-hydroxyvitamin D in the kidney (Fig. 8). The liver mitochondrial cytochrome P-450 was not active in the presence of microsomal NADPH-cytochrome P-450 reductase [135,136]. Ferredoxin reductase as well as ferredoxin were active regardless of whether they were isolated from rat liver mitochondria or bovine adrenal mitochondria [133]. The partially purified cytochrome P-450 had a carbon monoxide difference spectrum similar to that of microsomal cytochrome P-450 from liver microsomes and adrenal mitochondria. In the work by Pedersen et al. [133], the concentration of mitochondrial cytochrome P-450 in rat liver mitochondria from untreated rats was calculated to be only about 0.1 nmole/mg protein. Treatment of rats with phenobarbital increased the specific content of cytochrome P-450 in the mitochondria more than 2-fold, without significant increase in the 26-hydroxylase activity. The carbon monoxide spectrum of the reduced cytochrome P-450 solubilized from liver mitochondria of phenobarbital-treated rats exhibited a spectral shift of about 2 nm as compared to the corresponding spectrum obtained in analysis of preparations from untreated rats. This was taken as evidence that more than one species of cytochrome P-450 was present in the preparation. It was later shown by Pedersen et al. [137] and Bjbrkhem et al. [138] that the preparation was also able to catalyse 25-hydroxylation of vitamin D3 and that different enzymes are involved in... 

Cycloaddition of 2-pyrones 5 to vinyl ethers 6 serves a key reaction in the synthesis of the important chiron 9, being an A-ring precursor to la-hydroxyvitamin D3. The best diastereose-lectivities were obtained when the appropriate chiral auxiliary was used in the diene component22 or a stereochemically matched pair of chiral diene and chiral catalyst was applied22. 

The MS-free BINOL-Ti complex 21 catalyzes the inverse-electron-demand Diels Alder reaction of methyl 2-pyrone-3-carboxylate (23) with vinyl ethers 24, yielding adducts 25 in 95-98% ee and excellent yields39. The adducts are converted into an important synthon for la-hydroxyvitamin D3. 

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. 

Extrarenal expression of 25-hydroxyvitamin Dj-la-hydroxylase. J. Clin. Endocrinol. Metab. 86, 888-894. 

The ontogeny of 25-hydroxyvitamin Dj la-hydroxylase expression in human placenta and decidua. Am. J. Pathol. 161, 105-114. 

F. Vilchis, and F. Larrea (2002). Expression and activity of 25-hydroxyvitamin D-la-hydroxylase are restricted in cultures of human syncytiotro-phoblast cells from preeclamptic pregnancies. J. Clin. Endocrinol. Metab. 87, 3876-3882. 

Friedrich, M., C. Villena-Heinsen, R. Axt-Fliedner, R. Meyberg, W. Tilgen, W. Schmidt et al. (2002). Analysis of 25-hydroxyvitamin Dj-la-hydroxylase in cervical tissue. Anticancer Res. 22, 183-186. 

Stimulation of 25-hydroxyvitamin Dj-la-hydro-xylase by phosphate depletion. J. Biol. Chem. 251,3158-3161. 

Bland, R., E.A. Walker, S.V. Hughes, P.M. Stewart, and M. Hewison (1999). Constitutive expression of 25-hydroxyvitamin Dj-la-hydroxylase in a transformed human proximal tubule cell line Evidence for direct regulation of vitamin D metabolism by calcium. Endocrinology 140, 2027-2034. 

Michigami, X, H. Yamato, H. Suzuki, Y. Nagai-Itagaki, K. Sato, and K. Ozono (2001). Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin Dj-la-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy. J. Endocrinol. 171, 249-257. 

PTH has stimulatory effects on bone and kidney, including the stimulation of la-hydroxylase activity in kidney mitochondria leading to the increased production of the biologically active hormone 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (see Figure 61-5). Solid lines indicate a positive effect dashed lines refer to negative feedback. 

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