Biochemistry and metabolism of vitamin D

Abstract

Vitamin D is not technically a vitamin, since it is not an essential dietary factor. It is rather a prohormone produced photochemically in the skin from 7-dehydrocholesterol. Vitamin D and its metabolites may be categorized as either cholecalciferols or ergocalciferols. Cholecalciferol (vitamin D3) is the parent compound of the naturally occurring family and is produced in the skin from 7-dehydrocholesterol on exposure to the ultraviolet B portion of sunlight. Vitamin D2 (ergocalciferol), the parent compound of the other family, is manufactured by irradiation of ergosterol produced by yeasts and its potency is less than one-third of vitamin D3's potency. The steps in the vitamin D endocrine system include the following: 1) the photoconversion of 7-dehydrocholesterol to vitamin D3 in the skin or dietary intake of vitamin D3; 2) metabolism of vitamin D3 by the liver to 25-hydroxyvitamin-D3 [25(OH)D3], the major form of vitamin D circulating in the blood compartment; 3) conversion of 25(OH)D3 by the kidney (functioning as an endocrine gland) to the hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]; 4) systemic transport of the dihydroxylated metabolite 1,25(OH)2D3 to distal target organs; and 5) binding of 1,25(OH)2D3 to a nuclear receptor (VDR) at target organs, followed by generation of appropriate biological responses. The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hydroxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1a-hydro xylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1,25(OH)2D3. A five-step inactivation pathway from 1,25(OH)2D3 to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally induced in vitamin D target cells by the action of 1,25(OH)2D3. An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein (DBP), which carries vitamin D3 and its metabolites to their metabolism and target organs. DBP is a specific, high-affinity transport protein. It is synthesized by the liver and circulates in great excess, with fewer than 5% of the binding sites normally occupied. 1,25(OH)2D3, acts as a ligand for a nuclear transcription factor, vitamin D receptor - VDR, which like all other nuclear receptors, regulates gene transcription and cell function. The widespread presence of VDR, and the key activating (1a-hydroxylase, CYP27B1) and inactivating (24-hydroxylase, CYP24A1) enzymes in most mammalian cells means that the cells in these tissues have the potential to produce biological responses, depending on the availability of appropriate amounts of vitamin D3. Thanks to this widespread presence of elements of vitamin D endocrine system, its biological features are being recognized outside bone tissue, i.e. calcium and phosphate metabolism.

Vitamin D nije pravi vitamin, odnosno nije esencijalni dijetetski faktor, već je pre prohormon koji nastaje fotohemijskom reakcijom u koži iz 7-dehidroholesterola. Vita min D i njegovi metaboliti mogu da se kategorizuju kao holekalciferoli ili ergokalciferoli. Holekalciferol (vitamin D3) je polazno jedinjenje za familiju koja se nalazi u prirodi i produkuje se u koži iz 7-dehidroholesterola pri izlaganju ultraljubičastom B delu spektra sunčeve svetlosti. Vitamin D2 (ergokalciferol), polazno jedinjenje druge familije, nastaje radijacijom ergosterola koga produkuju kvasci i ima samo jednu trećinu aktivnosti vitamina D3. Faze u endokrinom sistemu vitamina D su: 1) fotokonverzija 7-dehidroholesterola u vitamin D3 u koži ili unos vitamina D3-hranom; 2) metabolizam vitamina D3 u jetri do 25-hidroksivitamina D3 [25(OH)D3], glavnog oblika vitamina D u cirkulaciji; 3) konverzija 25(OH)D3 u bubregu (koji ovde funkcioniše kao endokrina žlezda) do hormona 1,25-dihidroksivitamin D3 [1,25(OH)2D3]; 4) sistemski transport dihidroksi-metabolita do distalnih ciljnih organa; i 5) vezivanje 1,25(OH)2D3 za nuklearni receptor (VDR) u ciljnim organima, što prati odgovarajući biološki odgovor. Aktivacija vitamina D do hormonskog oblika je posredovana citohrom P450 enzimima. Pokazano je da šest izoformi citohroma P450 (CYP) učestvuje u hidroksilaciji vitamina D. Za četiri od njih, CYP27A1, CYP2R1, CYP3A4 i CYP2J3, se pretpostavlja da imaju aktivnost 25-hidroksilaze koja uče s tvuje u prvom koraku aktivacije. Renalni enzim, 25-hidroksivitamin D-1a-hidroksilaza sa strogo regulisanom aktivnošću, predstavlja CYP27B1, koji završava aktivaciju do hormonskog oblika 1,25(OH)2D3. Proces inaktivacije, koji se sastoji iz pet stupnjeva od 1,25(OH)2D3 do kalcitroične kiseline, obavlja jedan multifunkcionalni CYP, CYP24A1, čija je transkripcija indukovana u ciljnim ćelija carbonma dejstva vitamina D posredstvom 1,25(OH)2D3. Dodatna ključna komponenta u dejstvu vitamin D endokrinog sistema je vitamin D vezujući protein u plazmi (DBP), koji transportuje vitamin D3 i njegove metabolite do ciljnih i organa gde se odvija njihov metabolizam. DBP je specifičan transportni protein velikog afiniteta. Sintetiše se u jetri i cirkuliše u velikom višku, sa zasićenjem vezujućih mesta manjim od 5%. 1,25(OH)2D3 deluje kao ligand nuklearnog transkripcionog faktora, VDR, koji reguliše transkripciju gena i funkciju ćelija. široka rasprostranjenost VDR i ključnih enizma aktivacije (1a-hidroksilaza, CYP27B1) i inaktivacije (24-hidroksilaza, CYP24A1) u većini ćelija sisara znači da ćelije u ovim tkivima imaju potencijal za produkovanje bioloških odgovora, zavisno od raspoloživosti dovoljnih ko li čina vitamina D3. Zahvaljujući rasprostranjenosti elemenata endokrinog sistema vitamina D, njegove biološke oso bi ne se prepoznaju i izvan koštanog sistema, odnosno metabolizma kalcijuma i fosfora.