Book Volume 1
Page: i-i (1)
Author: Terry Opgenorth
Page: ii-ii (1)
Author: J. Ruth Wu-Wong
Page: iii-iii (1)
Author: J. Ruth Wu-Wong
Page: 3-11 (9)
Author: Masahide Mizobuchi
The discovery of the vitamin D system, which plays an important role in maintaining the health of living beings, has made significant contributions to the medical field. Immediately after the discovery, it was postulated that vitamin D (cholecalciferol or ergocalciferol) was not active, and did not have any physiological function. It was subsequently found that vitamin D needs to be metabolized in the liver and kidney by hydroxylation to be transformed into an active form. Subsequently it was shown that most of the physiological functions of the active form of vitamin D are mediated by a nuclear receptor, the vitamin D receptor (VDR), to exert genomic actions to control expression of various VDR target genes. Furthermore, although the active form of vitamin D was originally considered to be mainly a hormone that regulates mineral metabolism, it is now recognized that active vitamin D is a hormone involved in modulating numerous physiological functions based on the wide distribution of VDR in various cells and tissues in the human body. This recognition is supported by many studies that demonstrate the correlation between abnormal vitamin D metabolism and numerous pathological conditions. In chronic kidney disease (CKD) patients with impaired vitamin D metabolism, the most significant cause of death is cardiovascular complications, suggesting an important role of the vitamin D-VDR axis in maintaining cardiovascular function. Thus, in addition to the development of vitamin D analogs for the treatment of bone disease and hyperparathyroidism secondary to CKD, the application of vitamin D analogs for treating cardiovascular disease in CKD has been attracting attention.
Page: 12-25 (14)
Author: Petya Valcheva and Jose M. Valdivielso
Vitamin D is a seco-steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of the bone. In addition to its endocrine effects, vitamin D has important autocrine/paracrine roles. The last step in the activation of vitamin D, the hydroxylation on Carbon 1, takes place mainly in the kidney. However, extra-renal sites have been also found to exhibit 25-hydroxyvitamin D3-1-α-hydroxylase activity. The hormonally active form of vitamin D (1,25(OH)2D3, or calcitriol) mediates its biological effects by binding to the vitamin D receptor, a nuclear receptor. After the receptor is activated by calcitriol or its analogs, the protein changes its tridimensional conformation, which leads to key processes in mediating its nuclear actions such as binding to specific DNA sites to modify the expression of target genes. Several steps take place in order to increase or decrease the transcription rate of a target gene. First, homodimerization of the vitamin D receptor or heterodimerization with the retinoid X receptor allows the complex to bind to DNA. Then, several proteins are recruited to the complex that either increase or decrease chromatin condensation, thus acting like co-represors or co-activators, respectively, finally decreasing or increasing the target gene transcription. The co-activators bind to several extra proteins that build a bridge to the basal transcriptional machinery. Therefore, little changes in the receptor’s tridimensional structure elicited by different analogs can lead to differences in protein recruitment and in gene transactivation. Furthermore, differences in the cellular environment can yield different responses to the same analog. This characteristic of the nuclear receptors makes them good candidates as valuable therapeutic targets.
Page: 26-40 (15)
Author: Csaba P. Kovesdy
Vitamin D deficiency has emerged as a potential risk factor for multiple adverse outcomes, including cardiovascular and cancer related morbidity and mortality. Epidemiological studies have been instrumental in detecting associations between lower serum levels of vitamin D and such outcomes, and by doing so have provided an impetus to examine the mechanisms of action underlying such associations and to design interventional trials of vitamin D supplementation to try and reverse the adverse effects attributed to low serum vitamin D. This chapter reviews in detail observational studies that describe the incidence and prevalence of hypovitaminosis D, and the various adverse outcomes that low serum vitamin D has been linked with. The comprehensive nature of this review will provide the reader with a better understanding of why vitamin D is currently regarded as a very promising area of research to try and lower adverse outcomes in a variety of patient groups and in the general population.
Page: 41-56 (16)
Author: Alan H. Lau and Yee Ming Lee
There has been a recent plethora of studies uncovering the newly discovered physiological and pharmacological effects of vitamin D. With an increasing recognition of hypovitaminosis D worldwide, there is much interest to address the clinical significance of vitamin D deficiency and identify the most optimal regimen to replenish the body stores through supplementation. With our growing understanding of the non-mineral/bone activities of vitamin D, such as its effects on immune system, cancer and cardiovascular disease, there is a need to establish the optimal means of assessing vitamin D sufficiency and deficiency, the amount of vitamin D needed for optimal body function and how much vitamin D supplementation is required among individuals. As vitamin D is a pre-hormone that can both be synthesized in the body and obtained from the diet, there are challenges in deriving a recommendation. In addition, the amount of vitamin D present in the body is also influenced by factors such as aging, skin pigmentation, concomitant interacting medications and renal disease. For now, 25(OH)D is commonly used to determine vitamin D body stores in studies and clinical practice. This chapter seeks to discuss the issues surrounding vitamin D supplementation in the light of these new findings and address the concern over the vitamin D deficiency with the view that “more vitamin D is not necessarily better”.
Page: 57-82 (26)
Author: Gui-Dong Zhu
Since the discovery of 1α,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D, in early 1970s, research in the vitamin D endocrine system has received increasing attention. The biological actions of calcitriol have subsequently been shown to extend well beyond its classical functions in calcium homeostasis to include immune and angiogenesis, cell cycle, apoptosis, as well as endocrine regulations. While calcitriol demonstrates significant efficacy in treating hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism), its calcemic activity limits a broader therapeutic application of this vitamin D hormone. The medicinal chemistry efforts have primarily been directed to the differentiation of the desired therapeutic activity from the toxic episodic effects. More than three thousands vitamin D derivatives have been synthesized and some of them showed separation of the beneficial activities from calcemic effects. Nine vitamin D compounds have been approved in the United States, Japan or Europe for a number of indications. This review attempts to serve as a progress report for the vitamin D analogs currently on the market and in clinical development.
Page: 83-101 (19)
Author: Alex J. Brown
The vitamin D endocrine system was originally discovered for its critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), promotes intestinal absorption of calcium and phosphate, but actions on bone, kidney and the parathyroids also contribute to the control of mineral metabolism. Subsequently, the vitamin D receptor (VDR) was detected in many other target tissues where calcitriol exerts pleiotropic effects, often in an autocrine/paracrine fashion. These non-classical activities of calcitriol have suggested therapeutic applications of calcitriol for the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). In many cases, however, the effective therapeutic doses of calcitriol are hypercalcemic, a limitation that has spurred the development of vitamin D analogs that retain the therapeutically useful actions of calcitriol, but with reduced calcemic activity. Analogs with wider therapeutic windows are available for treatment of psoriasis and secondary hyperparathyroidism in chronic kidney disease, and research on even more effective analogs for these indications continues. Pre-clinical and clinical trials of analogs for treatment of several types of cancer, autoimmune disorders, and many other diseases are underway. Newer analogs show promise in various cellular models, but this review will focus on analogs currently in use and those with documented efficacy in animal models or in clinical trials.
Page: 102-116 (15)
Author: J. Ruth Wu-Wong
Emerging evidence suggests that vitamin D plays important roles in modulating cardiovascular, immunological, metabolic and other functions. However, numerous questions remain unanswered about the vitamin D-VDR axis. For example, is vitamin D a vitamin? Is it a hormone? Or is it both vitamin and hormone depending on whether it is the precursor or the active metabolite? Current clinical practices focus on measuring 25(OH)D deficiency in the blood. One important question that needs to be addressed is whether 25(OH)D is a proper marker for gauging VDR activation or not. It is well recognized that 25(OH)D is a precursor of the active form of vitamin D, calcitriol; 25(OH)D itself is not effective in activating VDR. In addition, studies have shown that, beside deficiency in vitamin D or 25(OH)D, many other factors such as disease, aging, gene polymorphism, etc. also impact vitamin D metabolism and VDR activation. Is there a need to develop biomarkers that can measure the deficiency in VDR activation at the molecular level so that the root of the problem can be properly corrected? Although vitamin D and its analogs are potentially useful for preventing and treating various diseases, their usage at this point is still rather limited. It is partially due to the fact that there is no way to distinguish whether the lack of effect of vitamin D and its analogs in clinical studies is due to inadequate activation of VDR or a general lack of efficacy. Biomarkers and assays to determine deficiency in VDR activation will be very useful. Another potential issue is that current on-the-market vitamin D analogs used to treat diseases such as hyperparathyroidism secondary to chronic kidney disease, psoriasis and osteoporosis have narrow therapeutic index and considerable side effects. New vitamin D analogs that have a wider therapeutic index without the hypercalcemic liability will allow the expanded usage of this class of drugs into new indications. As the field continues to evolve and new technology advances, the potential of vitamin D and its analogs for the prevention and treatment of various disorders will likely be realized in the near future.
Page: 117-120 (4)
Author: J. Ruth Wu-Wong
New tests and studies continue to reveal exciting information about the power of vitamin D in maintaining good health and preventing major illnesses. ‘Why Does Vitamin D Matter?’ not only covers vitamin D basics, but also explores the science of the vitamin D receptor (VDR), the protein that binds to the active metabolite of vitamin D to fulfill biochemical functions, it explains how vitamin D analogs directly activate the VDR. Readers will find this e-book informative, not only from the scientific point of view, but also from the potential applications of the knowledge into one’s daily life. Starting with a brief history of vitamin D and VDR research, followed by a detailed scientific report of how vitamin D and VDR work, this e-book goes on to cover epidemiological studies that investigate the outcome of vitamin D deficiency and the effects of vitamin D supplementation. Issues related to vitamin D supplementation are also addressed from different angles. This e-book continues with a comprehensive report on the numerous vitamin D analogs currently on the market or in development to treat various diseases, followed by exploring the possibility of developing this class of compounds for additional indications. This e-book is suitable for both general readers and scientists involved in vitamin D research or students who are interested in a career in biochemical/medical/nutritional research, especially in the field of vitamin D and the vitamin D receptor.
Scopus, Book Citation Index, Science Edition, BIOSIS Previews, Chemical Abstracts, EBSCO, Ulrich's Periodicals Directory