Biochemistry and metabolism of vitamin D / Biohemija i metabolizam vitamina D

Summary 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 (vi - tamin 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-hy - droxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1a-hy - dro 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 in du - ced 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) en - zy mes in most mammalian cells means that the cells in these tissues have the potential to produce biological res pon ses, depending on the availability of appropriate amounts of vi - tamin 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 pho - sphate metabolism. Kratak sadržaj Vitamin D nije pravi vitamin, odnosno nije esencijalni dijetetski faktor, ve} je pre prohormon koji nastaje fotohemijskom reakcijom u ko`i 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 ko`i iz 7-dehidroholesterola pri izlaganju ultraljubi~astom B delu spektra sun~eve svetlosti. Vitamin D2 (ergokalciferol), polazno jedinjenje druge familije, nastaje radijacijom ergosterola koga produkuju kvasci i ima samo jednu tre}inu aktivnosti vitamina D3. Faze u endo krinom sistemu vitamina D su: 1) fotokonverzija 7- dehidroholesterola u vitamin D3 u ko`i ili unos vitamina D3 hranom; 2) metabolizam vitamina D3 u jetri do 25-hidro - ksivitamina D3 [25(OH)D3], glavnog oblika vitamina D u cirkulaciji; 3) konverzija 25(OH)D3 u bubregu (koji ovde funkcioni{e kao endokrina `lezda) do hormona 1,25-di - hidroksivitamin 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, {to prati odgovaraju}i biolo{ki odgovor. Akti - vacija vitamina D do hormonskog oblika je posredovana citohrom P450 enzimima. Pokazano je da {est izoformi ci - tohroma P450 (CYP) u~estvuje u hidroksilaciji vitamina D. Za ~etiri od njih, CYP27A1, CYP2R1, CYP3A4 i CYP2J3, se pretpostavlja da imaju aktivnost 25-hidroksilaze koja u~e s tvuje u prvom koraku aktivacije. Renalni enzim, 25-hi - droksivitamin D-1a-hidroksilaza sa strogo regulisanom aktiv no{}u, predstavlja CYP27B1, koji zavr{ava aktivaciju do hormonskog oblika 1,25(OH)2D3. Proces inaktivacije, koji se sastoji iz pet stupnjeva od 1,25(OH)2D3 do kalci - troi~ne kiseline, obavlja jedan multifunkcionalni CYP, CYP24A1, ~ija je transkripcija indukovana u ciljnim }elijacarbonma dejstva vitamina D posredstvom 1,25(OH)2D3. Dodatna klju~na komponenta u dejstvu vitamin D endokrinog sistema je vitamin D vezuju}i protein u plazmi (DBP), koji transportuje vitamin D3 i nje gove metabolite do ciljnih i organa gde se odvija njihov meta bolizam. DBP je specifi~an transportni protein velikog afi ni teta. Sinteti{e se u jetri i cirkuli{e u velikom vi{ku, sa zasi}enjem vezuju}ih mesta manjim od 5%. 1,25(OH)2D3 deluje kao ligand nuklearnog transkripcionog faktora, VDR, koji reguli{e transkripciju gena i funkciju }elija. {iroka ras pro stranjenost VDR i klju~ - nih enizma aktivacije (1a-hidro ksi laza, CYP27B1) i inaktivacije (24-hidroksilaza, CYP24A1) u ve}ini }elija sisara zna~i da }elije u ovim tkivima imaju potencijal za produkovanje biolo{kih odgovora, zavisno od rasplo`ivosti dovoljnih ko li ~i - na vitamina D3. Zahvaljuju}i rasprostranjenosti elemenata endokrinog sistema vitamina D, njegove biolo{ke oso bi ne se prepoznaju i izvan ko{tanog sistema, odnosno meta bo - lizma kalcijuma i fosfora.