Vitamin D Review Plan
Introduction
In order to have a healthy body, people must be able to have vitamin intakes. There are various types of vitamins that should be consumed by an individual and each vitamin has different functions. One of these is Vitamin D also known as calciferol, is a fat-soluble vitamin which is attained through diet or simply by exposure to sun light. The human body can generate Vitamin D; sunlight produces a reaction creating vitamin D3 (cholecalciferol) converted by the liver and kidneys into biologically active metabolites. This procedure is so resourceful that according to the UK Government's Committee on Medical Aspects of Food Policy Panel on Dietary Reference Values 'No dietary intake (of Vitamin D) is essential for individuals living a regular lifestyle. The primary goal of this research is to conduct a review plan about vitamin D, its functions, and importance.
Sources and forms of Vitamin D
Humans acquire vitamin D from food sources making this vitamin a unique one among the major vitamins. There are two sources and forms of vitamin D. These are the exogenous, wherein vitamin D is produce from food sources (diet) and the endogenous wherein vitamin D is taken from sunlight.
1.1.1 Exogenous (diet)
The exogenous Vitamin D2 is a form of Vitamin D which is derived from plant and produced exogenously by irradiation of ergosterol and enters the ciculation of the body through diet (Wolpowtiz & Gilchrest, 2006). The primary function of Vitamin D in human body is to keep the right balance of calcium and phosphorous to sustain the bone that promotes strong bones. Similar to large amount of nutrients, vitamin D does not work without help. This is most efficient when cooperating with other vitamins, minerals and hormones to develop bone mineralization. The most frequent food source of vitamin D is milk. This is not a usual incidence; milk is fortified with vitamin D. Milk is loaded in calcium; therefore it is vital to make sure enough vitamin D helps your body absorb the calcium. In the study of Nowson and his collegues (2004), margarine is the only food in Australia which is widely utilised and consists of vitamin D via fortification.
1.1.2 Endogenous
It can be said that vitamin D is not a real vitamin because sufficient amounts can be achieved completely all the way through non-food sources. For example, many farmers and other outdoors workers get their needed vitamin D straight from the sun throughout definite times of year. Accordingly, the main source of vitamin D is the exposure to sunlight. For instance, in Australia, there are seasonal variations in the status of Vitamin D, such that serum 25-OHD degrees are considered to be lower at the end of winter as compared to the end of summer (Nowson et al, 2004). In the study made among Australians. It has been found that exposure of the whole body surface for 10-15 minutes in noonday sunlight is comparable to taking around 15000 IU of oral vitamin D.
1.2 Vitamin D Metabolism
Skin, liver and Kidneys
There has been much advancement in our understanding of the metabolism of vitamin D. Vitamin D3 can be developed in the skin or consumed in the food you eat. It gathers very rapidly in the liver where it go through 25-hydroxylation, yielding 25-OH-D3, the major circulating metabolite of the vitamin. 25-OH-D3 goes on to the kidney where it undertakes one of two hydroxylations. If there is a biological need for calcium or for phosphate the kidney is stimulated to translate 25-OH-D3 to the 1,25-(OH)2-D3, a calcium and phosphate assembling hormone. If the animal has enough storage of calcium and phosphate, the l-hydroxylase is lock up and as an alternative the 25-OH-D3 is exchanged to a 24,25-(OH)2D3. The function of the 24, 25-(OH)2D3 is not yet known; it possibly a transitional in the inactivation-excretion devices. 1, 25-(OH) 2D3 keeps going to intestine where it stimulates intestinal calcium transportation and intestinal phosphate transportation. It also arouses bone calcium mobilization and most likely has further results yet to be determined in such tissues as muscle. The 25-OH-D3-l-hydroxylase, which is positioned exclusively in renal mitochondria, has been shown to be a three component system relating a flavoprotein, an iron-sulfur (Iqbal, 1994) protein (renal ferredoxin), and a cytochrome P-450. This scheme has been effectively solubilized, the mechanisms isolated, and represented. The 24-hydroxylase, on the other hand, has not yet been carefully deliberated. 1, 25-(OH)2D3 is required for the manifestation of the 24-hydroxylase; parathyroid hormone contains 24-hydroxylation. It is probable that the 24-hydroxylase stands for the main synchronized enzyme, thus, its occurrence or absence may establish whether 1,25-(OH)2D3 is attained.
Two metabolic passageways for 1,25-(OH)2D3 are recognized, alteration by the 24-hydroxylase to 1, 24, 25-(OH) 3D3, and translation of 1,25-(OH)2D3 to an unidentified matter. In the final example, there arises failure of a side series part, plus no less than one of the 26 and 27 carbons. Whether 1,25-(OH)2D3 have to be metabolized more before it brings out all of its purposes has yet to be found. The major emission way of vitamin D3 is through the bile into the feces. Urinary excretion comes out little in amount and no emission materials have yet been recognized completely.
Much remains to be studied regarding the metabolism and purpose of vitamin D and its metabolites. Then must therefore, confirm to be a productive part of examination for numerous years to come, particularly since 1,25-(OH)2D3, 25-OH-D3, and lalpha-OH-D3 have been revealed to be efficient in a number of metabolic bone disorder states.
1.2.4 Regulation of Vitamin D Metabolism
Vitamin D and PTH are main hormones that regulate calcium metabolism. Also, the serum level of phosphorus is known to change according to the level of calcium and to regulate the vitamin D and PTH. Recently, cloning of 1alpha- hydroxylase cDNA which is the key enzyme in vitamin D metabolism enabled us to examine the effects of phosphorus in vitamin D metabolism at a molecular level. Furthermore, the direct effect of phosphorus in PTH synthesis is being elucidated in recent reports. In this paper, we summarized the regulation of vitamin D and PTH by phosphorus (Duso, Brown & Slatopolsky, 2005). In a study conducted by Hewison and his colleagues (2000), they have mentioned that the noticeable widespread distribution of mRNA and protein for 1_-Ohase in both extra-renal and renal tissues has raised essential issues which concern the local enzyme activity at this region. The connection between actual synthesis of 1,25-(OH)2D3 and expression of 1_-OHase in a specific tissue probably involves two particular mechanisms. These include the substrate access and the auto regulation of 1_-OHase function by 1,25-(OH)2D3 itself.
The previous questions the notion that, in common with other steroid hormones 1,25(OH)2D3 enter cells through a passive mechanism by virtue of the so-called lipophilic nature. The latter provides the plausibility that local 1_-OHase functions in extra-renal tissues is under even firmer control than that observed with the endocrine enzyme and, hence, local generation of 1,25-(OH)2D3 in vivo may be complex to identify various of serum proteins, however, by far the most essential of these is the vitamin D-binding protein (DBP), that is synthesized in the liver part. Previous investigations in vitro have recommended that DBP-bound vitamin D metabolites have restricted access to target cells and with these, the free formations of Vitamin D metabolites, with greater obvious accessibility target cells are more biologically functional and operational (Hewison et al, 2000; Dusso, Brown & Slatopolsky, 2005). However, analysis of the DBP null mouse has mentioned that the animals in the experiment were less vulnerable than the wild type to vitamin D-induced hypercalcaemia (Safadi et al. 1999). The DBP null mice also generated vitamin D deficiency much earlier than the experimented normal litter-mates. Taken together, the result of this study recommends that, in addition to its role as a transport protein, DBP also plays an essential function in directing vitamin D responses. Specifically, because of its significantly high capability for binding 25-(OH)2D3, DBP is probable to be a vital aspects of the availability of substrate to 1_-OHase. Current investigations have identified that DBP and DBP-bound vitamin D metabolites are filtered by the glomerulus and reabsorbed through the luminal endocytic receptor megalin (gp330) in the proximal tubules (Nykjaer et al. 1999).
Accordingly, megalin is included to the family of low-density-lipoprotein receptor gene (Saito et al. 1994) and is expressed in various types of tissues (Lundgren et al. 1997). Furthermore, megalin has also been identified to be found in the brush border membrane of the proximal tubules, while cells of the distal nephron seem to be noted as megalin-negative (Lundgren et al. 1997). Hence, megalin-mediated endocytosis of DBP bound 25(OH)D can act as an additional mechanism that control tissue-specific synthesis of 1,25(OH)2D3 by modifying the accessibility of substrate to the 1_-OHase protein. Such result may give a partial explanation for the inconsistency between more discrete patterns of actual enzyme activity in vivo and widespread 1_-OHase protein expression along the nephron.
Some studies have noted that, during vitamin D sufficiency, 1,25-(OH)2D3 generation by the kidneys is regulated very tightly regulated, however there is a remarkable up-regulation of 1_-OHase activity in proximal tubule cells in vitamin D-deficient states (Hewison et al, 2000). This reaction appears to be an activity of several direct and indirect systems which include changes in accessory proteins like ferrodoxin, or changes in VDR or 24-OHase expression. Some studies in vivo suggest that the vital activator of 1_-OHase is a PTH and that this impact is mediated, at least in the region, by target-cell induction of cAMP (Henry & Luntao, 1989).
Latest studies give emphasis capable cAMP reaction components in downstream regions that are PTH receptive in promoter–reporter assays (Kong et al. 1999; Brenza et al. 1998,). In these researches, the authors have not been able to show any self-regulation of basal CYP1_ promoter function, and no vitamin D response elements (VDREs) were also determined in the 1·4 kb fragment. But, in each condition 1,25-(OH)2D3 was able to suppress PTH induced trans-activation. Such findings recommends either that the CYP1_ gene promoter has a nonconforming VDRE, or that 1,25(OH)2D3 attains its effects through indirect mechanism. Such result contrast with investigation of the murine promoter (Murayama et al. 1998), that demonstrated both positive (PTH) and negative (1,25-(OH)2D3) receptiveness in a region downstream of –0·9 kb. Herein, calcitonin was identified to be a potent stimulator of 1_-OHase expression that support previous studies in which calcitonin was shown to stimulate 1_-OHase mRNA and operates under normocalcaemic situations (Shinki et al. 1999).
The study recommends that calcitonin, acting through distal sites of the nephron, may play an essential role in the ‘fine-tuning’ of serum 1,25-(OH)2D3 degrees in time of vitamin D sufficiency. Along with the most important inhibitors of 1_-OHase are phosphate, calcium, and 1,25-(OH)2D3 itself, the latter also invigorating an increase in 24-OHase function (Murayama et al. 1999).
In this study, it shows that most of these impacts s are mediated indirectly via modulation of PTH production and secretion. But, as a result of the tight regulation of 1,25-(OH)2D3 production, the result of the specific mechanisms involved in manipulating 1_-OHase has proven to be difficult. In addition, utilising a transformed human proximal tubule cell line, HKC-8, the studies confirmed the cAMP mediated up-regulation of 1_-OHase expression and inhibition of expression by 1,25-(OH)2D3 (Bland et al. 1999). Nevertheless, the study also noted that the most forceful and fast modulation of 1_-OHase expression and operation happened as a follow-up to changes in extra-cellular calcium. Comparatively high levels of calcium (2 mM versus 1 mM) decreased the synthesis of 1,25(OH)2D3, while significantly low levels (0·5 mM versus 1 mM) increased the enzyme activity. Such reactions happened within 4 h but were transitory, with operations returning to normal at 24 h. These experiments, coupled with the broad range expression of calcium-sensing receptors, along the nephron recommend that alterations in local calcium sensing may perform as a major variable of tissue-specific 1,25(OH)2D3 production. Moreover, another approach to the in vitro investigation of 1_-OHase has been to utilise preparations of keratinocytes or activate macrophages as oneo f the sources of 1_-OHase activity. In this regard, the major complexity connected with these model systems is that present evidence recommends that there are substantial discrepancies between the regulation of 1_-OHase in the kidney and that in extra-renal regions. For instance, , the synthesis of 1,25(OH)2D3 by activated macrophages is not repressed by 1,25(OH)2D3, and this seems to be the basis for the unregulated 1_-OHase operation connected with granulomatous diseases including sarcoidosis, and which often leads to hypercalcaemia in these victims. This is not easy to explain, specifically in view of recent researches which suggest that renal and extra-renal 1_-OHase is due to the equal gene product. Macrophage-like cells are considered to express VDR, and few groups have shown functional responses to 1,25(OH)2D3 in these cells (Hewison & O’Riordan 1997). Hence, the most likely illustration is that induction of extra-renal 1_- OHase engages regulatory pathways that is not the same from renal, cAMP-mediated mechanisms and are less sensitive to auto-regulation by 1,25(OH)2D3. Consequently, induction of extra-renal 1_-OHase often involves antigenic activators like lipopolysaccharide or inflammatory mediators like interferon-_. Since these agents signal via nuclear factor _B, Hewison and his colleagues (2000) can postulate that this direction activates 1_-OHase in a way unlike that of calciotrophic aspects and, as a effect, shows differential sensitivity to feedback control by 1,25(OH)2D3. In addition, analysis of the signal-transduction directions involved in regulating 1_-OHase will be critical to the comprehension of the way in which 1,25(OH)2D3 functions in extra-renal tissues (Hewison et al, 2000).
Transport of Vitamin D
Vitamin D receptor
It has been noted that during the past 10 years, receptors for 1,25-(OH)2 vitamin D3 (1,25-(OH)2D3) have been described in fetal rat calvaria (Stern, 1990), in primary cultures of calvarial cells with predominantly osteoblastic characteristics from both neonatal mice (Chen, Hirst & Feldman, 1979) and fetal rats (Stern, 1990), in rat and human osteogenic sarcoma cell lines and in cloned mouse osteoblastic cells. the binding sites have sedimentation coefficients of approximately 3.2 S, and high affinities for 1.25-(OH)2D3, with Kd’s in the 0.1 to 0.3 nM range (Stern, 1990). The concentration of binding sites was generally found to be less than 100 fmol/mg cytosolic protein. Receptor densities were highest at the start of culture (Stern, 1990). Examination of the time course of receptor binding indicated that in cell derived from neonatal mouse bone there was a correlation with the stage of the cell cycle, the number of receptors being highest during the log phase and lowest at confluence (&-8). In contrast, in bone cells from fetal rats the receptor concentration did not correlate with the cell cycle, showing a somewhat inverse correlation with thymidine incorporation. At the times when receptor density was highest, the concentration of binding sites in the rat bone cells was approximately 1/5 that in the mouth cells (Stern, 1990).
The binding sites in the various bone cells exhibit saturation. The selectivity for the ligands is consistent with the biological potencies of the various analogs and metabolites, 1,25-(OH)2D3 being the most potent with 25-OH-D3 and 24,25-(OH)2D3 being at least two orders of magnitude significantly affected the concentration of binding sites, however, the effects of glucocorticoid treatment on receptor number were again different in cells derived from mouse and rat tissues. In mouse bone cells, dexamethasone, 130 nM , decreased the receptor number, both in the log phase of growth and at confluence (Stern, 1990). Incorporation of 14C-thymidine was markedly inhibited by dexemethasone at the log phase but not at confluence. In contrast, glucocorticoids increased the density of 1,25-(OH)2D3 receptors in cells derived from fetal rat bone (3) and in fetal rat calvarial cells (11). In the rat bone cells, the effect was consistent throughout the cycle, with no effects of glucocorticids on thymidine incorporation (3). It ws proposed that glucocorticoids maintain the content of 1,25-(OH)2D3 receptors in rat bone cells by inhibiting their degradation.
The biochemical receptor studies suggest that the osteoblast is a target cell for 1,25-(OH)2D3 . in addition, thaw-mount autoradiographic studies in 18 to 20 day old rat fetuses injected with 3H-1,25-(OH)2D3 demonstrated the presence of radioactivity in the nuclei of osteoblasts and osteoprogenitor cells (Stern, 1990). This accumulation of radioactivity was selectively blocked by 1,25-(OH)2D3. in contrast, no labeling was observed in mature multinucleated osteoclasts (12). Other evidence suggesting that the osteoblast rather than the osteoclast is the target for 1,25-(OH)2D3 action was obtained with enriched populations of mature rat osteoblasts incubated on inert surfaces. The addition of 1,25-(OH)2D3 was ineffective in increasing the motility of isolated mature osteoclasts (Stern, 1990). However, the osteoclasts were activated to resorbed cortical bone slices when co-cultured with osteoblastic cells, in addition to 1,25-(OH)2D3 (Stern, 1990). The effect was abolished by inhibitors of macromolecular factor that promotes bone resorption was released when osteoblasts were treated with 1,25-(OH)2D3 (14). These results in isolated cell populations would be consistent with the model of Rodan and Martin, whereby the effects of 1,25-(OH)2D3 to elicit resorption by a direct effect on bone (Stern, 1990) could be elicited by an initial effect on the osteoblast, which would then activate the osteoclast to produce a local humorial mediator.
An alternative pathway for the direct effects of 1,25-(OH)2D3 on bone could be through increases in the numbers of osteoclasts. Evidence from several models indicated that osteoclasts arise from mononucleated hematogenous precursor cells that also develop into cells of the monocyte-macrophage lineage (Stern, 1990). Furthermore, 1,25-(OH)2D3 promotes the differentiation of monocytic cells, such as normal mouse alveolar macrophages and HL-60 promyelocytic leukemia cells, as well as primate marrow mononuclear cells with osteoclast characteristics including multinuclearity and tartrate-resistant acid phosphatase activity (20-22). These findings support the possibility that the direct effect of 1,25-(OH)2D3 on bone resorption could be mediated through an effect on osteoclast differentiation and maturation. This model would appear ti be inconsistent with the results of several recent studies in which 1,25-(OH)2D3 analogs with potencies greater than or equal to that of 1,25-(OH)2D3 on differentiation including 25-oxa-1α,25-(OH)2D3, 24,24-dihimo-1,25-(OH)2D3 and ∆22-24, 24 trihoma-1,25-(OH)2D3, MC 903 and 1, 25-dihydroxy-16-ene-23-yne-vitamin D3. These compounds have greater relative effects on differentiation than on bone resorption in vitro or production of hypercalcaemia in vivo, some even being inactive in eliciting resorptive and calcemic responses at concentrations several orders of magnitude higher than maximally effective concentrations of 1,25-(OH)2D3. 1,25-(OH)2D3 receptors have been shown to interact with DNA cellulose and as will described several of the effects of 1,25-(OH)2D3 on bone have been shown to be mediated through genomic actions. The report of a rapid transient effect of low concentrations of 1,25-(OH)2D3 to increase intracellular calcium in mouse osteoblasts raises the possibility of the existence of non-genomic second messenger effects. But, in another study, short term treatment with this metabolite failed to increase calcium influx in bone cells.
Biological Actions of Vitamin D on target tissues and Systems
The maintenance of serum calcium and phosphate levels as well as the provision of minerals for bone formation by 1,25(OH)2D3 is largely mediated by the hormone’s intestinal activities. One if the best-defined effects of 1,25(OH)2D3 is the stimulation of the intestinal lumen-plasma flux of calcium and phosphate. Extensive evidence exists for an interaction of 1,25(OH)2D3 with an intestinal receptor and for genome-mediated up-regulation of a calcium-binding protein, known a s calbindin-D. The amounts of calbindin-D in the intestinal mucosa in both humans and animals are positively correlated with the rate of calcium transport or absorption; however, studies have not yet defined the exact role of calbindin-D in this process (DeLuca, Krisinger & Darwish, 1990). In addition to the genomic actions of the hormone, emerging evidence supports the existence of a nongenomic stimulation of intestinal calcium transport by 1,25(OH)2D3 that is very rapid.
Bone tissue undergoes construct remodelling, in that under normal conditions the osteoclast-mediated resorption of bone is in approximate equilibrium with the osteoblast-mediated formation of new bone material. A variety of local and systemic hormonal modulators have been implicated in the short-term and long-term regulation of these dual processes, 1,25(OH)2D3 is well characterized as an essential hormone for the regular mineralization of new bone and as a potent bone-resorptive agent.
The 1,25(OH)2D3 -induced stimulation of bone growth and mineralization probably is not mediated through a direct effect on osteoblasts. Evidence suggests that 1,25(OH)2D3 stimulates bone mineralization indirectly by providing minerals for incorporation into bone matrix through increased intestinal absorption of calcium and phosphorus. On the other hand, osteoblasts, which possess 1,25(OH)2D3 receptors, are probably the primary target cells for 1,25(OH)2D3 in bone. Accordingly, a spectrum of osteoblast-related functions has been shown to be influenced by 1,25(OH)2D3 (Reichel et al, 1989). For example, 1,25(OH)2D3 modulated the proliferation of and alkaline phosphatase production in cultured osteoblasts, increased the synthesis of osteoblasts-derived bone y-carboxyglutamic acid protein (osteocalcin) and of matrix y carboxyglutamic acid protein, and down-regulated the production of type I collagen by fetal rat calvaria. Recently, investigators have demonstrated a 1,25(OH)2D3-mediated increased of receptors for epidermal growth factor B-like activity of osteoblast. Thus, 1,25(OH)2D3 seems to play a part in the regulation of osteoblast function; however, the physiologic relevance of such interactions (e.g., for osteoblast- mediated processes of bone remodelling) must be defined more precisely (Reichel et al, 1989)..
The bone-resorbing effects of 1,25(OH)2D3 probably can be divided into short-term and long-term actions. There is evidence the neither effect is exerted directly on the mature osteoclast. With respect to ling-term effects, investigators have shown that the administration of 1,25(OH)2D3 to rats results in an increased formation of osteoclasts in vivo over a period of several days. Studies in vitro have indicated that the number of osteoclast-like cells increased in long-term culture of primate bone marrow cells after exposure to 1,25(OH)2D3 for 14 to 21 days. Most of the available data suggest that the osteoclast originates from a hematopoietic cell of macrophage lineage. Therefore, the increase in osteoclast induced by 1,25(OH)2D3 may indicate a maturational effect of the hormone on myeloid hematopoietic precursor cells, in that these cells are prompted to different entiate toward functional osteoclasts. Consistent with the postulate that 1,25(OH)2D3 alters the number but not the function of the osteoclasts, chicken osteoclasts have been reported not to contain 1,25(OH)2D3 receptors. These findings may represent a case in which the ability of 1,25(OH)2D3 to induce cellular differentiation is closely linked to its effects on mineral metabolism.
The short-term effects of 1,25(OH)2D3 on bone resorption have been demonstrated in organ cultures of bone; the 1,25(OH)2D3-mediated release of calcium from bone was demonstrable after several hours. This effect was too rapid to be explained by the ability of the hormone to increase the pool of osteoclasts. The exact mechanism of this short-term mobilization of calcium from bone is not known but evidence suggests that 1,25(OH)2D3 induces the release of osteoblast-derived resorption factors that stimulate osteoclast activity.
Probably the most important effect of 1,25(OH)2D3 on the kidney is the inhibition of 25(OH)D3-l-α-hydroxylase activity, which result in a decrease of 1,25(OH)2D3 biosynthesis. This effect is accompanied by a stimulation of 25 (OH)D3-24-hydroxylase. The hormone has also been implicated in the regulation of renal calcium and phosphate excretion. There is controversy, however, about the direction (increased excretion vs. increased resorption) of a possible 1,25(OH)2D3 -mediated effect and on the conditions in which the hormone interferes with renal calcium and phosphate transport. Clearly, more research is needed to determine the effects of 1,25(OH)2D3 on the kidney in addition to its modulation of the 25(OH)D3-hydroxylases (Reichel et al, 1989)..
Factors influence Vitamin D levels
Vitamin D deficiency
Definition of vitamin D deficiency
Criteria of definition of Vitamin D deficiency
Populations at risk for Vitamin D deficiency
Disorder of Vitamin D metabolism
Reference
Brenza HL, Kimmel-Jehan C, Jehan F, Shinki T, Wakino S, Anazawa H et al. (1998) Parathyroid hormone activation of the 25-hydroxyvitamin D3-1 alpha-hydroxylase gene promoter. PNAS 95 1387–1391.
Chen, TL, Hirst, MA, and Feldman, D. A receptor-like binding macromolecule for 1α, 25-Dihydroxy Vitamin D3 receptors in cultured rat osteoblast-like cells. Journal of Biological Chem, 258:4350-4355.
DeLuca, HF, Krisinger, J. & Darwish, H. (1990). The Vitamin D System: 1990. Kidney International 38, suppl. 29, S-2: S-8.
Dusso, AS, Brown, AJ and Slatopolsky, E. Vitamin D. Am J Physiol Renal Physiol 289: F8–F28.
Henry HL & Luntao EM (1989) Interactions between intracellular signals involved in the regulation of 25-hydroxyvitamin D3 etabolism. Endocrinology 124 2228–2234.
Hewison M & O’Riordan JLH (1997). Immunomodulatory and cell differentiation effects of vitamin D. In Vitamin D, pp 447–462. Eds D Feldman, FH Glorieux & JW Pike. San Diego: Academic Press.
Hewison, M., Zenhnder, D., Bland, R. & Stewart, PM (2000). 1_-Hydroxylase and the action of vitamin D. Journal of Molecular Endocrinology, 25, 141–148
Iqbal, SJ (1994). Vitamin D metabolism and the Clinical aspects of measuring metabolites. Ann Clinical Biochem, 31: 109-124.
Kong XF, Zhu XH, Pei YL, Jackson DM & Holick MF (1999). Molecular cloning, characterization, and promoter analysis of the human 25-hydroxyvitamin D3-1 alpha-hydroxylase gene. PNAS 96 6988–6993.
Lundgren S, Carling T, Hjalm G, Juhlin C, Rastad J, Pihlgren U, Rask L, Akerstrom G & Hellman P (1997). Tissue distribution of human gp330/megalin, a putative Ca2+ sensing protein. Journal of Histochemistry and Cytochemistry 45 383–392.
Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T & Kato S (1998). The promoter of the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1_,25(OH)2D3. Biochemical and Biophysical Research Communications 249 11–16.
Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen E & Willnow T 1999 An endocytic pathway essential for renal uptake and activation of the steroid 25(OH)vitamin D3. Cell 96 507–515.
Reichel, H., Koeffler, P., Norman, A.W. (1989). The Role of the Vitamin D Endocrine System in Health and Disease. The New England Journal of Medicine, 320:15
Safadi F, Thornton P, Magiera H, Hollis B, Gentile M, Haddad J, Liebhaber S & Cooke N (1999). Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. Journal of Clinical Investigation 103, 239–251.
Saito A, Pietromanaco S, Lao AK-C & Farquhar MG (1994). Complete cloning and sequencing of rat gp330/‘megalin’, a distinctive member of the low density lipoprotein receptor gene family. PNAS 91 9725–9729
Shinki T, Ueno Y, DeLuca HF & Suda T (1999). Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3 1_-hydroxylase gene in normocalcemic rats. PNAS 96 8253–8258.
Stern, PH (1990). Vitamin D and Bone. Kidney International, 38: 29. S-17-S21.
