The Physiology and Pathophysiology of Vitamin D
1985; Elsevier BV; Volume: 60; Issue: 12 Linguagem: Inglês
10.1016/s0025-6196(12)64791-0
ISSN1942-5546
Autores Tópico(s)Bone health and osteoporosis research
ResumoThe vitamin D endocrine system plays an important role in the maintenance of normal calcium homeostasis. Abnormalities of this system occur in many conditions, such as rickets, osteomalacia, hypoparathyroidism, and hyperparathyroidism. The diagnosis and treatment of these disorders will be facilitated if the clinician understands the general mechanisms by which defects in vitamin D metabolism and action occur. We review this information and discuss the use and limitations of vitamin D metabolite assays for diagnosis of clinical disorders of mineral metabolism. The vitamin D endocrine system plays an important role in the maintenance of normal calcium homeostasis. Abnormalities of this system occur in many conditions, such as rickets, osteomalacia, hypoparathyroidism, and hyperparathyroidism. The diagnosis and treatment of these disorders will be facilitated if the clinician understands the general mechanisms by which defects in vitamin D metabolism and action occur. We review this information and discuss the use and limitations of vitamin D metabolite assays for diagnosis of clinical disorders of mineral metabolism. Vitamin D plays a central role in the maintenance of calcium homeostasis.1DeLuca HF The metabolism, physiology, and function of vitamin D.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 1-68Google Scholar, 2Kumar R Metabolism of 1,25-dihydroxyvitamin D3.Physiol Rev. 1984; 64: 478-504Crossref PubMed Google Scholar In its absence, hypocalcemia occurs and the maintenance of skeletal integrity is impaired. The classic vitamin D-deficiency disorders are rickets in children and osteomalacia in adults. The vitamin, by means of its active metabolite, promotes the efficient absorption of calcium from the intestine, the proper mineralization of bone, and the maintenance of normal calcium levels. The vitamin D endocrine system and parathyroid hormone play important and interrelated roles in the maintenance of calcium homeostasis in humans and various other species. Vitamin D is metabolized to more polar, biologically active products in the liver and kidney. The production of the active form of the vitamin, 1,25-dihydroxyvitamin D, is regulated by the calcium and phosphorus requirements of the body. In this review, we will discuss the manner in which vitamin D is metabolized, the means by which the production of the active metabolite is controlled, and the mechanisms by which various diseases perturb the metabolism of the sterol. Vitamin D (for the purposes of this article, the term "vitamin D" will encompass both vitamin D2 and vitamin D3; when appropriate, we will refer to the individual forms of the vitamin) is obtained from dietary sources and from endogenous synthesis of a precursor substance. The major form of vitamin D in the body is vitamin D3. Dietary vitamin D is absorbed in the upper part of the small intestine in much the same way as are other fat-soluble compounds.3Hollander D Muralidhara KS Zimmerman A Vitamin D-3 intestinal absorption in vivo: influence of fatty acids, bile salts, and perfusate pH on absorption.Gut. 1978; 19: 267-272Crossref PubMed Google Scholar, 4Dueland S Pedersen JI Helgerud P Drevon CA Transport of vitamin D3 from rat intestine: evidence for transfer of vitamin D3 from chylomicrons to α-globulins.J Biol Chem. 1982; 257: 146-150PubMed Google Scholar It enters the circulation primarily through the thoracic duct in the chylomicron fraction, after which it associates with an α-globulin fraction in the blood. In addition to being present in the diet, vitamin D3 is formed from a precursor, 7-dehydrocholesterol, which is present in large amounts in the skin.5Windaus A Bock F Über das Provitamin aus dem Sterin der Schweineschwarte.Hoppe Seylers Z Physiol Chem. 1937; 245: 168-170Crossref Google Scholar, 6Holick MF The photobiology of vitamin D3 in man.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 197-216Google Scholar 7-Dehydrocholesterol is converted to vitamin D3 under the influence of ultraviolet light that is present in normal sunlight.7Windaus A Schenck F von Werder F Über das antirachitisch wirksame Bestrahlungsprodukt aus 7-Dehydro-cholesterin.Hoppe Seylers Z Physiol Chem. 1936; 241: 100-103Crossref Google Scholar, 8Steenbock H Black A Fat-soluble vitamins. XVII. The induction of growth-promoting and calcifying properties in a ration by exposure to ultra-violet light.J Biol Chem. 1924; 61: 405-422Abstract Full Text PDF Google Scholar As long ago as 1919, Huldschinsky9Huldschinsky K Heilung von Rachitis durch künstliche Höhensonne.Dtsch Med Wochenschr. 1919; 45: 712-713Crossref Google Scholar showed that rickets could be cured simply by exposure of the affected patient to sunlight. The formation of vitamin D3 from 7-dehydrocholesterol involves the opening of the B ring of 7-dehydrocholesterol and the production of an intermediate, previtamin D3, which undergoes thermal rearrangement to the vitamin6Holick MF The photobiology of vitamin D3 in man.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 197-216Google Scholar, 10Esvelt RP Schnoes HK DeLuca HF Vitamin D3 from rat skins irradiated in vitro with ultraviolet light.Arch Biochem Biophys. 1978; 188: 282-286Crossref PubMed Google Scholar, 11Holick MF Richtand NM McNeill SC Holick SA Frommer JE Henley JW Potts Jr, JT Isolation and identification of previtamin D3 from the skin of rats exposed to ultraviolet irradiation.Biochemistry. 1979; 18: 1003-1008Crossref PubMed Scopus (76) Google Scholar (Fig. 1). The vitamin has a relatively high affinity for a transport protein (vitamin D-binding protein) present in blood, and investigators have suggested that the vitamin is carried out of the skin bound to this carrier moiety, whereas the previtamin that has a low affinity for the binding protein remains in the skin.6Holick MF The photobiology of vitamin D3 in man.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 197-216Google Scholar The amount of exposure to sunlight influences the amount of vitamin D3 formed. Serum levels of vitamin D3 and its metabolite, 25-hydroxyvitamin D3, are higher during the summer than during the winter, when exposure to sunlight is limited.6Holick MF The photobiology of vitamin D3 in man.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 197-216Google Scholar Factors other than the duration of exposure to sunlight also influence the amount of vitamin D3 formed from 7-dehydrocholesterol. Dark skin pigmentation decreases the amount of vitamin formed after exposure to sunlight.6Holick MF The photobiology of vitamin D3 in man.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 197-216Google Scholar, 12Clemens TL Adams JS Henderson SL Holick MF Increased skin pigment reduces the capacity of skin to synthesise vitamin D3.Lancet. 1982; 1: 74-76Abstract PubMed Google Scholar Unlike vitamin D3, vitamin D2 is not formed in the skin but is obtained only from dietary sources. Vitamin D2 is formed by the conversion of a plant sterol, ergosterol, to the vitamin. Once vitamin D enters the circulation, it is bound by an α2-globulin known as vitamin D-binding protein.4Dueland S Pedersen JI Helgerud P Drevon CA Transport of vitamin D3 from rat intestine: evidence for transfer of vitamin D3 from chylomicrons to α-globulins.J Biol Chem. 1982; 257: 146-150PubMed Google Scholar, 6Holick MF The photobiology of vitamin D3 in man.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 197-216Google Scholar Vitamin D is not active as such but undergoes a series of metabolic transformations first in the liver and then in the kidney to form the active metabolite, 1,25-dihydroxyvitamin D.1DeLuca HF The metabolism, physiology, and function of vitamin D.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 1-68Google Scholar, 2Kumar R Metabolism of 1,25-dihydroxyvitamin D3.Physiol Rev. 1984; 64: 478-504Crossref PubMed Google Scholar In the liver, an enzyme, vitamin D-25-hydroxylase, converts vitamin D to 25-hydroxyvitamin D (Fig. 2).13Blunt JW DeLuca HF Schnoes HK 25-Hydroxycholecalciferol: a biologically active metabolite of vitamin D3.Biochemistry. 1968; 7: 3317-3322Crossref PubMed Scopus (378) Google Scholar, 14Ponchon G DeLuca HF The role of the liver in the metabolism of vitamin D.J Clin Invest. 1969; 48: 1273-1279Crossref PubMed Google Scholar This enzyme is located in both the microsomal and the mitochondrial fractions of the hepatocyte.15Bhattacharyya MH DeLuca HF Subcellular location of rat liver calciferol-25-hydroxylase.Arch Biochem Biophys. 1974; 160: 58-62Crossref PubMed Google Scholar, 16Björkhem I Holmberg I Assay and properties of a mitochondrial 25-hydroxylase active on vitamin D3.J Biol Chem. 1978; 253: 842-849Abstract Full Text PDF PubMed Google Scholar The mitochondrial enzyme is not regulated by the vitamin D status of the organism, whereas the microsomal enzyme is partially controlled by previously formed vitamin D metabolites.16Björkhem I Holmberg I Assay and properties of a mitochondrial 25-hydroxylase active on vitamin D3.J Biol Chem. 1978; 253: 842-849Abstract Full Text PDF PubMed Google Scholar, 17Bhattacharyya MH DeLuca HF The regulation of rat liver calciferol-25-hydroxylase.J Biol Chem. 1973; 248: 2969-2973Abstract Full Text PDF PubMed Google Scholar As a result, the most important factor in determining the amount of 25-hydroxyvitamin D in the plasma or serum is the amount of vitamin D present in the plasma from either dietary or endogenous sources. Consequently, the plasma or serum 25-hydroxyvitamin D level is an accurate reflection of vitamin D reserve in the human. 25-Hydroxyvitamin D is not biologically active in physiologic amounts but undergoes transformation to the active form, 1,25-dihydroxyvitamin D18Lawson DEM Fraser DR Kodicek E Morris HR Williams DH Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism.Nature. 1971; 230: 228-230Crossref PubMed Scopus (68) Google Scholar, 19Holick MF Schnoes HK DeLuca HF Suda T Cousins RJ Isolation and identification of 1,25-dihydroxycholecalciferol: a metabolite of vitamin D active in intestine.Biochemistry. 1971; 10: 2799-2804Crossref PubMed Scopus (338) Google Scholar, 20Norman AW Myrtle JF Midgett RJ Nowicki HG Williams V Popjak G 1,25-Dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine.Science. 1971; 173: 51-54Crossref PubMed Google Scholar (Fig. 3), in the mitochondria of cells in the proximal tubule of the kidney.21Fraser DR Kodicek E Unique biosynthesis by kidney of a biologically active vitamin D metabolite.Nature. 1970; 228: 764-766Crossref PubMed Scopus (145) Google Scholar, 22Brunette MG Chan M Ferriere C Roberts KD Site of 1,25(OH)2 vitamin D3 synthesis in the kidney.Nature. 1978; 276: 287-289Crossref PubMed Google Scholar The formation of 1,25-dihydroxyvitamin D is regulated by several factors, the most important of which are parathyroid hormone and serum inorganic phosphate23Garabedian M Holick MF DeLuca HF Boyle IT Control of 25-hydroxycholecalciferol metabolism by parathyroid glands.Proc Natl Acad Sci USA. 1972; 69: 1673-1676Crossref PubMed Google Scholar, 24Boyle IT Gray RW DeLuca HF Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol.Proc Natl Acad Sci USA. 1971; 68: 2131-2134Crossref PubMed Google Scholar, 25Adams ND Gray RW Lemann Jr, J The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults.J Clin Endocrinol Metab. 1979; 48: 1008-1016Crossref PubMed Google Scholar, 26Gray RW Wilz DR Caldas AE Lemann Jr, J The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects, in calcium-stone formers and in patients with primary hyperparathyroidism.J Clin Endocrinol Metab. 1977; 45: 299-306Crossref PubMed Google Scholar, 27Rasmussen H Wong M Bikle D Goodman DBP Hormonal control of the renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol.J Clin Invest. 1972; 51: 2502-2504Crossref PubMed Google Scholar, 28Tanaka Y DeLuca HF The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus.Arch Biochem Biophys. 1973; 154: 566-574Crossref PubMed Google Scholar, 29Henry HL Regulation of the hydroxylation of 25-hydroxyvitamin D3 in vivo and in primary cultures of chick kidney cells.J Biol Chem. 1979; 254: 2722-2729Abstract Full Text PDF PubMed Google Scholar, 30Kumar R Cohen WR Silva P Epstein FH Elevated 1,24-dihydroxyvitamin D plasma levels in normal human pregnancy and lactation.J Clin Invest. 1979; 63: 342-344Crossref PubMed Google Scholar, 31Pike JW Parker JB Haussler MR Boass A Toverud SU Dynamic changes in circulating 1,25-dihydroxyvitamin D during reproduction in rats.Science. 1979; 204: 1427-1429Crossref PubMed Google Scholar, 32Lorenc R Tanaka Y DeLuca HF Jones G Lack of effect of calcitonin on the regulation of vitamin D metabolism in the rat.Endocrinology. 1977; 100: 468-472Crossref PubMed Google Scholar, 33Emmertsen K Melsen F Mosekilde L Lund B Lund B Sorensen OH Nielsen HE Solling H Hansen HH Altered vitamin D metabolism and bone remodelling in patients with medullary thyroid carcinoma and hypercalcitoninemia.Metab Bone Dis Relat Res. 1981; 4: 17-23Abstract Full Text PDF Google Scholar, 34Lund B Sorensen OH Lund B Bishop JE Norman AW Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and hypocalcemia in man.J Clin Endocrinol Metab. 1980; 50: 480-484Crossref PubMed Google Scholar, 35Tanaka Y Castillo L DeLuca HF Control of renal vitamin D hydroxylases in birds by sex hormones.Proc Natl Acad Sci USA. 1976; 73: 2701-2705Crossref PubMed Google Scholar, 36Adams ND Garthwaite TL Gray RW Hagen TC Lemann Jr, J The interrelationships among prolactin, 1,25-dihydroxyvitamin D, and parathyroid hormone in humans.J Clin Endocrinol Metab. 1979; 49: 628-630Crossref PubMed Google Scholar, 37Kumar R Abboud CF Riggs BL The effect of elevated prolactin levels on plasma 1,25-dihydroxyvitamin D and intestinal absorption of calcium.Mayo Clin Proc. 1980; 55: 51-53PubMed Google Scholar, 38Spanos E Colston KW Evans MS Galante LS Macauley SJ Maclntyre I Effect of prolactin on vitamin D metabolism.Moll Cell Endocrinol. 1976; 5: 163-167Crossref PubMed Google Scholar, 39Spanos E Barrett D MacIntyre I Pike JW Safilian EF Haussler MR Effect of growth hormone on vitamin D metabolism.Nature. 1978; 273: 246-247Crossref PubMed Scopus (27) Google Scholar, 40Eskildsen PC Lund B Sorensen OH Lund B Bishop JE Norman AW Acromegaly and vitamin D metabolism: effect of bromocriptine treatment.J Clin Endocrinol Metab. 1979; 49: 484-486Crossref PubMed Google Scholar, 41Kumar R Merimee TJ Silva P Epstein FH The effect of chronic excess or deficiency of growth hormone on plasma 1,25-dihydroxyvitamin D levels in man.in: Norman AW Schaefer K von Herrath D Grigoleit H-G Coburn JW DeLuca HF Mawer EB Suda T Vitamin D: Basic Research and Its Clinical Application. Walter de Gruyter, New York1979: 1005-1009Google Scholar, 42Gertner JM Horst RL Broadus AE Rasmussen H Genel M Parathyroid function and vitamin D metabolism during human growth hormone replacement.J Clin Endocrinol Metab. 1979; 49: 185-188Crossref PubMed Scopus (61) Google Scholar, 43Mosekilde BJ Melsen F Lund B Lund B Sorensen OH Serum levels of vitamin D metabolites and bone remodelling in hyperthyroidism.Metabolism. 1982; 31: 126-132Abstract Full Text PDF PubMed Google Scholar, 44Bouillon R Muls E De Moor P Influence of thyroid function on the serum concentration of 1,25-dihydroxyvitamin D3.J Clin Endocrinol Metab. 1980; 51: 793-797Crossref PubMed Google Scholar, 45Kimberg DV Baerg RD Gershon E Graudusius RT Effect of cortisone treatment on the active transport of calcium by the small intestine.J Clin Invest. 1971; 50: 1309-1321Crossref PubMed Google Scholar, 46Favus MJ Walling MW Kimberg DV Effects of 1,25-dihydroxycholecalciferol on intestinal calcium transport in cortisone-treated rats.J Clin Invest. 1973; 52: 1680-1685Crossref PubMed Google Scholar, 47Feher JJ Wasserman RH Intestinal calcium-binding protein and calcium absorption in cortisol-treated chicks: effects of vitamin D3 and 1,25-dihydroxyvitamin D3.Endocrinology. 1979; 104: 547-551Crossref PubMed Google Scholar, 48Seeman E Kumar R Hunder GG Scott M Heath III, H Riggs BL Production, degradation, and circulating levels of 1,25-dihydroxyvitamin D in health and in chronic glucocorticoid excess.J Clin Invest. 1980; 66: 664-669Crossref PubMed Google Scholar, 49Adams ND Gray RW Lemann Jr, J The calciuria of increased fixed acid production in humans: evidence against a role for parathyroid hormone and 1,25(OH)2-vitamin D.Calcif Tissue Int. 1979; 28: 233-238Crossref PubMed Scopus (17) Google Scholar and perhaps serum calcium directly. The factors that alter the plasma concentrations or synthesis of 1,25-dihydroxyvitamin D are shown in Table 1. Many of them are important only in certain experimental models. Further details concerning the regulation of 25-hydroxyvitamin D-1α-hydroxylase are available in recently published reviews, and the interested reader is directed to them for information that is not presented in this article.1DeLuca HF The metabolism, physiology, and function of vitamin D.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 1-68Google Scholar, 2Kumar R Metabolism of 1,25-dihydroxyvitamin D3.Physiol Rev. 1984; 64: 478-504Crossref PubMed Google Scholar, 50DeLuca HF Schnoes HK Vitamin D: recent advances.Annu Rev Biochem. 1983; 52: 411-439Crossref PubMed Google Scholar, 51Fraser DR Regulation of the metabolism of vitamin D.Physiol Rev. 1980; 60: 551-613Crossref PubMed Scopus (0) Google Scholar, 52Haussler MR McCain TA Basic and clinical concepts related to vitamin D metabolism and action (first of two parts).N Engl J Med. 1977; 297: 974-983Crossref PubMed Google Scholar, 53Haussler MR McCain TA Basic and clinical concepts related to vitamin D metabolism and action (second of two parts).N Engl J Med. 1977; 297: 1041-1050Crossref PubMed Google Scholar The enzyme responsible for the metabolic transformation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is a complex that consists of nicotinamide-adenine dinucleotide phosphate reductase, renal ferredoxin, and cytochrome P450, whose characteristics have been well defined in the chick kidney.54Ghazarian JG DeLuca HF 25-Hydroxycholecalciferol-1-hydroxylase: a specific requirement for NADPH and a hemoprotein component in chick kidney mitochondria.Arch Biochem Biophys. 1974; 160: 63-72Crossref PubMed Google Scholar, 55Ghazarian JG Jefcoate CR Knutson JC Orme-Johnson WH DeLuca HF Mitochondrial cytochrome P450: a component of chick kidney 25-hydroxycholecalciferol-1α-hydroxylase.J Biol Chem. 1974; 249: 3026-3033Abstract Full Text PDF PubMed Google Scholar, 56Pedersen JI Ghazarian JG Orme-Johnson NR DeLuca HF Isolation of chick renal mitochondrial ferredoxin active in the 25-hydroxyvitamin D3-1α-hydroxylase system.J Biol Chem. 1976; 251: 3933-3941Abstract Full Text PDF PubMed Google ScholarTable 1Factors Altering Serum 1,25-Dihydroxyvitamin D Levels or 25-Hydroxyvitamin D-1α-Hydroxylase ActivityModified from Kumar R.2 By permission of the American Physiological Society.Effect*+ = stimulation or increase; – = suppression or decrease; 0 = no effect; ? = effect not known; 1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D. on 1,25(OH)2D levels or 25(OH)D-1α-hydroxylase activityFactorChangeIn animalsIn humansParathyroid hormoneIncrease++Decrease−−Serum inorganic phosphateIncrease−−Decrease++1,25-Dihydroxyvitamin D3Increase−?Decrease+?Calcium (direct)Increase??Decrease++CalcitoninIncrease+, −0+Decrease??H+Increase−0Decrease??Sex steroidsIncrease++Decrease??ProlactinIncrease+0Decrease??Growth hormoneIncrease+0, −, +Decrease??GlucocorticoidsIncrease−−, 0, +Decrease??Thyroid hormoneIncrease?−†Effects may be caused by changes in calcium, phosphorus, or parathyroid hormone.Decrease−+†Effects may be caused by changes in calcium, phosphorus, or parathyroid hormone.Pregnancy…++* + = stimulation or increase; – = suppression or decrease; 0 = no effect; ? = effect not known; 1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D.† Effects may be caused by changes in calcium, phosphorus, or parathyroid hormone. Open table in a new tab When hypocalcemia occurs, this perturbation is rapidly sensed by the parathyroid gland, and the secretion of parathyroid hormone is increased almost immediately.57Aurbach GD Marx SJ Spiegel AM Parathyroid hormone, calcitonin, and the calciferols.in: Williams RH Textbook of Endocrinology. Sixth edition. WB Saunders Company, Philadelphia1981: 922-1031Google Scholar This peptide hormone increases the mobilization of calcium from bone and also decreases the fractional excretion of calcium in the kidney. These effects occur quickly and increase the concentration of calcium in the blood. In addition to these changes, parathyroid hormone causes increased activity of the 25-hydroxyvitamin D- 1α-hydroxylase enzyme, which in turn enhances the synthesis of 1,25-dihydroxyvitamin D.23Garabedian M Holick MF DeLuca HF Boyle IT Control of 25-hydroxycholecalciferol metabolism by parathyroid glands.Proc Natl Acad Sci USA. 1972; 69: 1673-1676Crossref PubMed Google Scholar, 24Boyle IT Gray RW DeLuca HF Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol.Proc Natl Acad Sci USA. 1971; 68: 2131-2134Crossref PubMed Google Scholar, 25Adams ND Gray RW Lemann Jr, J The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults.J Clin Endocrinol Metab. 1979; 48: 1008-1016Crossref PubMed Google Scholar The latter substance increases the efficiency of absorption of calcium in the intestine and thereby brings more calcium into the body.58Omdahl J Holick M Suda T Tanaka Y DeLuca HF Biological activity of 1,25-dihydroxycholecalciferol.Biochemistry. 1971; 10: 2935-2940Crossref PubMed Google Scholar Additionally, in hypocalcemia, 1,25-dihydroxyvitamin D enhances the efficiency of calcium mobilization from bone, which also increases serum calcium levels.59Tanaka Y DeLuca HF Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D.Arch Biochem Biophys. 1971; 146: 574-578Crossref PubMed Google Scholar In the absence of parathyroid glands, the increase in 25-hydroxyvitamin D-1α-hydroxylase activity is absent or small.23Garabedian M Holick MF DeLuca HF Boyle IT Control of 25-hydroxycholecalciferol metabolism by parathyroid glands.Proc Natl Acad Sci USA. 1972; 69: 1673-1676Crossref PubMed Google Scholar Some investigators, however, have suggested that calcium may directly control the activity of the enzyme responsible for synthesizing 1,25-dihydroxyvitamin D.34Lund B Sorensen OH Lund B Bishop JE Norman AW Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and hypocalcemia in man.J Clin Endocrinol Metab. 1980; 50: 480-484Crossref PubMed Google Scholar The increase in synthesis of 1,25-dihydroxyvitamin D in response to hypocalcemia (via the secretion of parathyroid hormone) occurs within a few hours, whereas the parathyroid glands respond to hypocalcemia within a few minutes.57Aurbach GD Marx SJ Spiegel AM Parathyroid hormone, calcitonin, and the calciferols.in: Williams RH Textbook of Endocrinology. Sixth edition. WB Saunders Company, Philadelphia1981: 922-1031Google Scholar, 58Omdahl J Holick M Suda T Tanaka Y DeLuca HF Biological activity of 1,25-dihydroxycholecalciferol.Biochemistry. 1971; 10: 2935-2940Crossref PubMed Google Scholar In hypercalcemia, the secretion of parathyroid hormone is suppressed and the synthesis of 1,25-dihydroxyvitamin D is greatly diminished, whereas the synthesis of another inactive metabolite, 24, 25-dihydroxyvitamin D3, is augmented24Boyle IT Gray RW DeLuca HF Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol.Proc Natl Acad Sci USA. 1971; 68: 2131-2134Crossref PubMed Google Scholar, 25Adams ND Gray RW Lemann Jr, J The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults.J Clin Endocrinol Metab. 1979; 48: 1008-1016Crossref PubMed Google Scholar (Fig. 3, Fig. 4). The serum level of inorganic phosphate influences the amount of 1,25-dihydroxyvitamin D synthesized in a manner that is independent of parathyroid hormone. Hypophosphatemia increases the amount of 1,25-dihydroxyvitamin D synthesized.26Gray RW Wilz DR Caldas AE Lemann Jr, J The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects, in calcium-stone formers and in patients with primary hyperparathyroidism.J Clin Endocrinol Metab. 1977; 45: 299-306Crossref PubMed Google Scholar, 28Tanaka Y DeLuca HF The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus.Arch Biochem Biophys. 1973; 154: 566-574Crossref PubMed Google Scholar The increased 1,25-dihydroxyvitamin D enhances the amount of phosphate absorbed from the small intestine; thus, more phosphate enters the organism. In addition, during dietary phosphate depletion with its accompanying hypophosphatemia, serum calcium levels are higher than when the concentration of serum phosphate is normal. The hypercalcemia suppresses the secretion of parathyroid hormone and diminishes the phosphaturic effect of parathyroid hormone on the kidney.57Aurbach GD Marx SJ Spiegel AM Parathyroid hormone, calcitonin, and the calciferols.in: Williams RH Textbook of Endocrinology. Sixth edition. WB Saunders Company, Philadelphia1981: 922-1031Google Scholar Additionally, intrinsic renal mechanisms that are unrelated to parathyroid hormone or vitamin D enhance phosphate reclamation in hypophosphatemic states.57Aurbach GD Marx SJ Spiegel AM Parathyroid hormone, calcitonin, and the calciferols.in: Williams RH Textbook of Endocrinology. Sixth edition. WB Saunders Company, Philadelphia1981: 922-1031Google Scholar All these factors correct the hypophosphatemia. The opposite series of events occurs in hyperphosphatemia. The synthesis of 24,25-dihydroxyvitamin D3 is suppressed in hypophosphatemia and enhanced in hyperphosphatemia. The physiologic defenses that are activated during the perturbations of serum phosphorus levels are shown in Figure 5. The major organs affected by 1,25-dihydroxyvitamin D are the intestine and bone.1DeLuca HF The metabolism, physiology, and function of vitamin D.in: Kumar R Vitamin D: Basic and Clinical Aspects. Martinus Nijhoff Publishing, Boston1984: 1-68Google Scholar, 2Kumar R Metabolism of 1,25-dihydroxyvitamin D3.Physiol Rev. 1984; 64: 478-504Crossref PubMed Google Scholar, 58Omdahl J Holick M Suda T Tanaka Y DeLuca HF Biological activity of 1,25-dihydroxycholecalciferol.Biochemistry. 1971; 10: 2935-2940Crossref PubMed Google Scholar, 59Tanaka Y DeLuca HF Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D.Arch Biochem Biophys. 1971; 146: 574-578Crossref PubMed Google Scholar, 60Tanaka Y DeLuca HF Role of 1,25-dihydroxyvitamin D3 in maintaining serum phosphorus and curing rickets.Proc Natl Acad Sci USA. 1974; 71: 1040-1044Crossref PubMed Google Scholar In the intestine, the chief effect of this hormone is to increase the active transport of calcium.58Omdahl J Holick M Suda T Tanaka Y DeLuca HF Biological activity of 1,25-dihydroxycholecalciferol.Biochemistry. 1971; 10: 2935-2940Crossref PubMed Google Scholar It does this predominantly in the proximal part of the small intestine, although good evidence is now available that other parts of the intestine and colon also respond to physiologic amounts of this hormone. The stimulation of calcium transport by 1,25-dihydroxyvitamin D is an energy-dependent, sodium-requiring process.61Wasserman RH Kallfelz FA Comar CL Active transport of calcium by rat duodenum in vivo.Science. 1961; 133: 883-884Crossref PubMed Google Scholar, 62Martin DL DeLuca HF Influence of sodium on calcium transport by the rat small intestine.Am J Physiol. 1969; 216: 1351-1359Crossref PubMed Scopus (198) Google Scholar In the enterocyte, 1,25-dihydroxyvitamin D is rapidly localized in the nucleus.63Zile M Bunge EC Barsness L Yamada S Schnoes HK DeLuca HF Localization of 1,25-dihydroxyvitamin D3 in intestinal nuclei in vivo.Arch Biochem Biophys. 1978; 186: 15-24Crossref PubMed Google Scholar It is bound by a protein receptor that is predominantly located in the nucleus.64Brumbaugh PF Haussler MR 1α,25-Dihydroxy-cholecalciferol receptors in intestine. I. Association of 1α,25-dihydroxycholecalciferol with intestinal mucosa chromatin.J Biol Chem. 1974; 249: 1251-1257Abstract Full Text PDF PubMed Google Scholar, 65Brumbaugh PF Haussler MR 1α,25-Dihydroxycholecalciferol receptors in intestine. II. Temperature-dependent transfer of the hormone to chromatin via a specific cytosol receptor.J Biol Chem. 1974; 249: 1258-1262Abstract Full Text PDF PubMed Google Scholar Most likely, the receptor is needed for the actions of 1,25-dihydroxyvitamin D within the nucleus; however, investigators are uncertain about whether it is needed for the movement of 1,25-dihydroxyvitamin D into the nucleus itself. In the nucleus, the sterol incre
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