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

Bone metabolism and disease in chronic kidney disease

Background Elevated calcium and phosphorus levels after therapy with injectable vitamin D for secondary hyperparathyroidism may accelerate vascular disease and hasten death in patients undergoing long-term hemodialysis. Paricalcitol, a new vitamin D analogue, appears to lessen the elevations in serum calcium and phosphorus levels, as compared with calcitriol, the standard form of injectable vitamin D. Methods We conducted a historical cohort study to compare the 36-month survival rate among patients undergoing long-term hemodialysis who started to receive treatment with paricalcitol (29,021 patients) or calcitriol (38,378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratified analyses were performed. A subgroup of 16,483 patients who switched regimens was also evaluated. Results The mortality rate among patients receiving paricalcitol was 3417 per 19,031 person-years (0.180 per person-year), as compared with 6805 per 30,471 person-years (0.223 per person-year) am...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa022536

Survival of Patients Undergoing Hemodialysis with Paricalcitol or Calcitriol Therapy

Vitamin D insufficiency affects almost 50% of the population worldwide An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD) This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin High prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease As the number of people with VDD continues to increase, the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research VDD is very common in all age groups As few foods contain vitamin D, guidelines recommended supplementation at suggested daily intake and tolerable upper limit levels It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency Treatment with either vitamin D2 or vitamin D3 is recommended for deficient patients A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality In this review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and understand its biology and clinical implications

Vitamin D: The "sunshine" vitamin

Renal osteodystrophy

An LD50 of 0.2 mg/kg body wt has been determined for 1 alpha-hydroxyvitamin D3 in the rat. In comparison, the LD50 for 1 alpha-hydroxyvitamin D2 is between 3.5 and 6.5 mg/kg. In terms of chronic toxicity, 1 alpha-hydroxyvitamin D3 at a dose of 5 micrograms/kg/day causes death of one-half the animals in a 4-week period. On the other hand, 20 micrograms/kg/day of 1 alpha-hydroxyvitamin D2 is required to induce similar toxicity. The body weight record and renal calcium accumulation during chronic treatment support the above conclusion. It therefore appears that 1 alpha-hydroxyvitamin D2 is between 5 and 15 times less toxic than 1 alpha-hydroxyvitamin D3. This surprising result prompted a reexamination of the relative biological activity of 1 alpha-hydroxyvitamin D2 and 1 alpha-hydroxyvitamin D3. Both compounds are equally potent in the stimulation of intestinal calcium transport, bone calcium mobilization, in the elevation of serum phosphorus, and in the healing of rickets in the rat. The reason for lower toxicity of 1 alpha-hydroxyvitamin D2 is unknown. The results suggest that 1 alpha-hydroxyvitamin D2 might represent a therapeutically superior compound.

1α-Hydroxyvitamin D2 is Less Toxic than 1α-Hydroxyvitamin D3 in the Rat

This invention provides pharmaceutical uses for 2-methylene-19-nor-20(S)-1 alpha ,25-dihydroxyvitamin D>3<. This compound is characterized by high bone calcium mobilization activity demonstrating preferential activity on bone. This results in a novel therapeutic agent for the treatment of diseases where bone formation is desired, particularly osteoporosis. This compound also exhibits pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anticancer agent and for the treatment of skin diseases such as psoriasis. This compound also increases both breaking strength and crushing strength of bones eveidencing use in conjunction with boen replacement surgery such as hip and knee replacements.

USE OF 2-METHYLENE-19-NOR-20(S)-1 alpha ,25-DIHYDROXYVITAMIN D>3< TO INCREASE BONE STRENGTH

Compositions containing 19-nor-vitamin D compounds in a suitable carrier and methods employing such compositions are disclosed for cosmetic uses in the treatment of various skin conditions such as lack of adequate skin firmness, wrinkles, dermal hydration and sebum secretion. Various formulations of the compositions including creams, lotions and ointments are disclosed for use topically, orally or parenterally in accordance with this invention.

Cosmetic compositions containing 19-nor-vitamin D compounds

Compositions containing vitamin D compounds in a suitable carrier and methods employing such compositions are disclosed for cosmetic uses in the treatment of various skin conditions such as lack of adequate skin firmness, wrinkles, lack of dermal hydration and insufficient sebum secretion. Various formulations of the compositions including creams, lotions and ointments are disclosed for use topically, orally or parenterally in accordance with this invention.

Use of vitamin D compounds for the manufacture of a cosmetic composition and use of it for improvements of skin conditions

Chemical synthesis of (22E, 24R)- and (22E, 24S)-1, 24-dihydroxy-Δ22-vitamin D3 has been achieved starting with the commercially available dinorcholenic acid acetate. Synthesis involved introduction of the 1-hydroxy group by a reduction of the 1, 2-epoxide generated by epoxidation of the 1, 4, 6-trien-3-one. The side chain on the steroid was then constructed by means of a Wittig reaction followed by introduction of the Δ7 bond by standard methods and its protection with 1-phenyl-1, 2, 4-triazoline-3, 5-dione. Subsequent reduction of the hydroxy groups in the steroid side chain followed by reduction of the Diels-Alder addition products yielded the both 24-isomers. The 5, 7-dienes were irradiated and the corresponding vitamin D compounds isolated. Nuclear magnetic resonance was used to identify individual isomers. The (22E, 24S)-1, 24-hydroxyvitamin D3 compound bound equally well to the chick intestinal cytosol receptor as 1, 25-dihydroxyvitamin D3, while the 24R-isomer was approximately ten times less active. In vivo, both isomers were less active than 1, 25-dihydroxyvitamin D3 ; however, the 24S-isomer was considerably more active than the 24R-isomer approaching the activity of 1, 25-dihydroxyvitamin D3.

Smith Connie M

Papers

1α-Hydroxyvitamin D2 is Less Toxic than 1α-Hydroxyvitamin D3 in the Rat

USE OF 2-METHYLENE-19-NOR-20(S)-1 alpha ,25-DIHYDROXYVITAMIN D>3< TO INCREASE BONE STRENGTH

Cosmetic compositions containing 19-nor-vitamin D compounds

Use of vitamin D compounds for the manufacture of a cosmetic composition and use of it for improvements of skin conditions

Synthesis and biological activity of (22E,24R)- and (22E,24S)-1 alpha,24-dihydroxy-22-dehydrovitamin D3.