The important reactions that occur to the vitamin D molecule and the important reactions involved in the expression of the final active form of vitamin D are reviewed in a critical manner. After an overview of the metabolism of vitamin D to its active form and to its metabolic degradation products, the molecular understanding of the 1alpha-hydroxylation reaction and the 24-hydroxylation reaction of the vitamin D hormone is presented. Furthermore, the role of vitamin D in maintenance of serum calcium is reviewed at the physiological level and at the molecular level whenever possible. Of particular importance is the regulation of the parathyroid gland by the vitamin D hormone. A third section describes the known molecular events involved in the action of 1alpha,25-dihydroxyvitamin D3 on its target cells. This includes reviewing what is now known concerning the overall mechanism of transcriptional regulation by vitamin D. It describes the vitamin D receptors that have been cloned and identified and describes the coactivators and retinoid X receptors required for the function of vitamin D in its genomic actions. The presence of receptor in previously uncharted target organs of vitamin D action has led to a study of the possible function of vitamin D in these organs. A good example of a new function described for 1alpha,25-dihydroxyvitamin D3 is that found in the parathyroid gland. This is also true for the role of vitamin D hormone in skin, the immune system, a possible role in the pancreas, i.e., in the islet cells, and a possible role in female reproduction. This review also raises the intriguing question of whether vitamin D plays an important role in embryonic development, since vitamin D deficiency does not prohibit development, nor does vitamin D receptor knockout. The final section reviews some interesting analogs of the vitamin D hormone and their possible uses. The review ends with possible ideas with regard to future directions of vitamin D drug design.

Current Understanding of the Molecular Actions of Vitamin D

Pharmacokinetics of vitamin D toxicity

Photosynthesis of previtamin D3 can occur throughout the epidermis in the dermis when hypopigmented Caucasian skin is exposed to solar ultraviolet radiation. Once previtamin D3 is formed in the skin, it undergoes a temperature-dependent thermal isomerization that takes at least 3 days to complete. The vitamin D-binding protein preferentially translocates the thermal product, vitamin D3, into the circulation. These processes suggest a unique mechanism for the synthesis, storage, and slow, steady release of vitamin D3 from the skin into the circulation.

https://science.sciencemag.org/content/sci/210/4466/203.full.pdf

Photosynthesis of previtamin D3 in human skin and the physiologic consequences.

Introduction Vitamin D is generally accepted as being essential for life in higher animals (278). It is one of the most important biological regulators of calcium and phosphorus (406) metabolism. Along with the two peptide hormones PTH and calcitonin, vitamin D is responsible for the minute-to-minute as well as the day-to-day establishment and maintenance of calcium homeostasis. The substance vitamin D, or cholecalciferol, was first identified through the nutritional studies of Sir Edward Mellanby (243), which identified rickets as a disease state resulting from a deficiency of vitamin D, as well as through the biochemical/chemical studies of McCollum and co-workers (242), who demonstrated that there was more than one fat-soluble vitamin. Together these studies established a deficiency state, namely rickets, which was attributable to the newly discovered, nutritionally important fat-soluble component, vitamin D. In retrospect, however, the most important discovery related to the appreciation by Huldschins...

The vitamin D endocrine system: steroid metabolism, hormone receptors, and biological response (calcium binding proteins).

Beyond its established role in bone and mineral homeostasis, there is emerging evidence that vitamin D exerts a range of effects in skeletal muscle. Reports of profound muscle weakness and changes in the muscle morphology of adults with vitamin D deficiency have long been described. These reports have been supplemented by numerous trials assessing the impact of vitamin D on muscle strength and mass and falls in predominantly elderly and deficient populations. At a basic level, animal models have confirmed that vitamin D deficiency and congenital aberrations in the vitamin D endocrine system may result in muscle weakness. To explain these effects, some molecular mechanisms by which vitamin D impacts on muscle cell differentiation, intracellular calcium handling, and genomic activity have been elucidated. There are also suggestions that vitamin D alters muscle metabolism, specifically its sensitivity to insulin, which is a pertinent feature in the pathophysiology of insulin resistance and type 2 diabetes. We will review the range of human clinical, animal, and cell studies that address the impact of vitamin D in skeletal muscle, and discuss the controversial issues. This is a vibrant field of research and one that continues to extend the frontiers of knowledge of vitamin D's broad functional repertoire.

https://www.vitamindwiki.com/tiki-download_wiki_attachment.php?attId=2088

The roles of vitamin D in skeletal muscle: form, function, and metabolism.

The in vivo side-chain oxidation of 1 alpha,25-dihydroxyvitamin D3 was investigated by using a double-label radiotracer technique. Rats dosed with 1 alpha,25-dihydroxy-[3 alpha-3H]vitamin D3 and 1 alpha,25-dihydroxy[26,27-14C]vitamin D3 produced compounds with a high 3H/14C ratio. These compounds were found in sizable quantities in intestine and liver within 3 h after dosing. The major side-chain oxidized metabolite migrated as an acid on DEAE-Sephadex chromatography and contained no 14C. Methyl esterification of this compound with diazomethane proceeded in good yield and rendered the compound more amenable to chromatographic purification. The metabolite was isolated in several steps from rats dosed with 1 microgram of 1 alpha,25-dihydroxy[3 alpha-3H]vitamin D3. The metabolite was obtained in pure form as the methyl ester and was positively identified as 1 alpha,3 beta-dihydroxy-24-nor-9,10-seco-5,7,10(19)cholatrien-23-oic acid. The trivial name calcitroic acid is proposed for this major side-chain oxidized metabolite of 1,25-dihydroxyvitamin D3.

Isolation and characterization of 1 alpha-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D3.

Vitamin D3 from rat skins irradiated in vitro with ultraviolet light

A convenient, accurate assay was developed for determining skin cholesta-5,7-dien-3 beta-ol (7,8-didehydrocholesterol) concentrations. Ultraviolet spectrophotometry provided quantitation of the sterol from rat skins following saponification and chromatography on Lipidex and high-performance liquid chromatography. Correction for recoveries was accomplished by using 7,8-didehydro[3 alpha-3H]cholesterol as an internal standard. Chronic dosing of vitamin D-deficient rats with 1,25-dihydroxyvitamin D3 caused a 4-fold increase in skin 7-dehydrocholesterol content. This rise was not the result of changes in food consumption, body weight, or plasma calcium. Cholesterol concentrations were not significantly elevated although some of the other nonsaponifiable lipid components found in the high-performance liquid chromatogram appeared to be increased by the treatment. These results suggest that the vitamin D hormone 1,25-(OH)2D3 may exert a positive feedback regulation on the production of vitamin D3 in skin.

1,25-Dihydroxyvitamin D3 stimulated increase of 7,8-didehydrocholesterol levels in rat skin.

Calcitroic acid: Biological activity and tissue distribution studies

Metabolites of 1 alpha, 25-dihydroxy[3 alpha-3H]vitamin D3 in rat bile were studied. The water-soluble metabolites (77-91% of the total bile radioactivity) are predominantly acids (retained by DEAE-Sephadex chromatography) that become chloroform soluble after methylation with diazomethane. Calcitroic acid was isolated from this fraction (after conversion to the methyl ester) and unambiguously identified by chromatographic and mass spectrometric studies. The chloroform phase of extracted bile contains small amounts (1.1-8.1% of the metabolites in bile, dependent on dose given) of unchanged 1 alpha, 25-dihydroxyvitamin D3 and no 1 alpha, 24(R),25-trihydroxyvitamin D3. In addition, the chloroform phase contained a mixture of 24-dehydro- and 25-dehydro-1 alpha-hydroxyvitamin D3 and calcitroic acidmethyl ester. The latter compound was shown to be an artifact resulting from the use of methanol as part of the advent mixture for the initial bile extractions.

Robert P. Esvelt

Papers

Isolation and characterization of 1 alpha-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D3.

Vitamin D3 from rat skins irradiated in vitro with ultraviolet light

1,25-Dihydroxyvitamin D3 stimulated increase of 7,8-didehydrocholesterol levels in rat skin.

Calcitroic acid: Biological activity and tissue distribution studies

Metabolites of 1 alpha, 25-dihydroxyvitamin D3 in rat bile.