Regulation of CYP27B1 in the proximal renal tubule is controlled by PTH and fibroblast growth factor (FGF)-23, which stimulate and inhibit, respectively, its expression (Fig. 1,25(OH)2D within nonrenal tissues differs from that in the kidney. Although vitamin D receptor Tomatidine mediates the actions of 1 1,25(OH)2D, regulation of transcriptional activity is usually cell specific. 1,25(OH)2D inhibits PTH secretion but promotes insulin secretion, inhibits adaptive immunity but promotes innate immunity, and inhibits cell proliferation but stimulates their differentiation. Conclusions: The nonclassic actions of vitamin D are cell specific and provide a number of potential new clinical applications for 1,25(OH)2D3 and its analogs. However, the use of vitamin D metabolites and analogs for these applications remains limited by the classic actions of vitamin D leading to hypercalcemia and hypercalcuria. In the past few years, there has been growing appreciation for the many roles of vitamin D and its active metabolites in a large number of tissues. This has been stimulated by the appreciation that most tissues in the body have receptors for the active form of vitamin D, 1,25 dihydroxyvitamin D [1,25(OH)2D] or calcitriol. These receptors are named appropriately vitamin D receptors (VDRs), and tissues with VDR are potential target tissues. Furthermore, many of these tissues also contain the enzyme, CYP27B1, responsible for converting the major circulating metabolite of vitamin D, 25 hydroxyvitamin D (25OHD), to 1 1,25(OH)2D. Regulation of CYP27B1 in these nonrenal tissues generally differs from that in the kidney and may be more substrate dependent. Rabbit Polyclonal to NFYC This has led to the concept that maintenance of adequate 25OHD levels in the blood is required for vitamin D regulation of a large number of physiologic functions beyond that of the classic actions involved with bone mineral metabolism. This review is intended first to protect the basics of vitamin D production, metabolism, and molecular mechanism of action and then examine the impact of vitamin D and its metabolites on tissues that are not principally concerned with regulation of bone mineral metabolism. Two forms of vitamin D exist: vitamin D3 or cholecalciferol and vitamin D2 or ergocalciferol. The former is usually produced in the skin under the influence of UVB radiation (UVR); the latter is usually produced by UVR in a variety of plant materials and yeast (Fig. 1?1).). Differences exist in their binding to the major transport protein in blood, vitamin D binding protein, and in their metabolism because of the differences in the chemistry of their side chains, with the result that single doses of D2 lead to lower levels of circulating 25OHD than single doses of Tomatidine D3 (1,2), although daily administration of D2 and D3 maintains comparable levels of 25OHD (3). At the tissue level, these differences are minor in that the biologic activity of 1 1,25(OH)2D2 and 1,25(OH)2D3 appear to be comparable at least with respect to binding to VDR. Therefore, recommendations to vitamin D or D metabolites will refer to both forms unless normally indicated with a specific subscript. Open in a separate windows Physique 1 Production of vitamin D2 and vitamin D3. Ergosterol in plants and 7-dehydrocholesterol in skin are the precursors for vitamin D2 and vitamin D3, respectively. UV light B breaks the B chain of each molecule to form the pre-D isomer, which then undergoes isomerization to D. D2 and D3 differ only in the side chain in which D2 has a double bond between C22CC23 and a methyl group at C24. These differences alter somewhat its binding to DBP and metabolism. Vitamin D3 production Vitamin D3 (D3) is usually produced in the Tomatidine skin from 7-dehydrocholesterol through a two-step process in which the B ring is usually broken under UVR Tomatidine ( em e.g /em . sunlight), and the pre-D3 so formed isomerizes to D3 in a thermo-sensitive but noncatalytic process. Holick em et al /em . (4,5,6) exhibited that the formation of pre-D3 is usually relatively rapid, reaching a maximum within hours. Both intensity of UVR and level of pigmentation in the skin regulate the rate of pre-D3 formation but not the maximal level achieved. With continued UVR exposure, pre-D3 is usually converted to the biologically inactive lumisterol. Tachysterol is also created but, like pre-D3, does not accumulate Tomatidine with extended UVR. The formation of lumisterol and tachysterol is usually reversible and can be converted back to pre-D3 as pre-D3 levels fall. Thus, prolonged exposure to sunlight will not produce toxic amounts of D3 because of the photoconversion of pre-D3 to lumisterol and tachysterol as well as the photoconversion of D3 itself to suprasterols I and II and 5,6 transvitamin D3 (4). Melanin in the epidermis, by absorbing UVR, reduces D3 production. The intensity of UVR from sunlight varies according to season and latitude, so the farther one lives from your equator, the less time of the year one can rely on solar exposure to produce D3..