Vitamin D

The most common form of vitamin I) in foods is vitamin Di(9,10-seco(5Zt7E)-cholcsta-5.7.10( 19)-trien-3-ol, cholecatciferol. colecalciferol, oleov itarnin D,; molecular weight 384). The less common form vitamin D: (ergocalcifcrol) is slightly less effective.

Abbreviations

D2 vitamin Dj

D3 vitamin D^

DBP vitamin D-bindtng protein

25-D 25-hydroxyvitamin O

1,25-D 1u,25-dihydroxy-vitamtn D 24,25-D 24R,25-dihydro*y-vitamin D

PTH parathyroid hormone

UV-B ultraviolet B fight (290-315 nm)

Nutritional summary

Function: Promotes intestinal absorption of calcium and its retention in the body. Through its role in gene regulation the active form, l«.25-dihydroxy-vitamin D (1,25-Dj. it influences growth of bone and connective tissues and may protect against some forms of cancer.

Requirements: Adults should get at least 5 p.jz day, three times as much with advanced age.

Sources. Fatty fish and fortified milk are good dietary sources; eggs, fortified cereals, and fortified margarines contribute smaller amounts. A young person gets a lull day's supplies from 9— 1 fS minutes of face and arm exposure to summer sun (ultrav iolet B, UV-B. 290 315 tun), an older person needs several times longer exposure. Deficiency: A severe lack during childhood causes rickets, characterized by bone deformities in lower limbs (bowlegs) and chest. Deficiency at a later age causes loss of bone minerals (osteoporosis), in the most severe cases of both minerals and connective tissue (osteomalacia). Tetany and severe bone pain are characteristic signs. People with suboptimal vitamin D status tend to have elevated parathyroid hormone levels and absorb dietary calcium less well. Indicative symptoms for mild \ itamin I> deficiency Include fatigue, muscle ache, and diffuse bone pain (Nykjaer el at,T 2001). Excessive intake: Prolonged consumption of several hundred micrograms per day may cause hypercalcemia and soft tissue calcification. Continued exposure to doses of thousands of micrograms daily may cause coma and death in extreme cases.

Endogenous sources

Exposure of skin to ultraviolet light with wavelengths between 290 and 315 nm (UV-B) converts some of the cholesterol precursor 7-dehydrocholesterol to previtamin Di. which rearranges spontaneously to vitamin D» (Holick ei at., 19891. Suberythemal (a dose that does not cause sunburn) irradiation of skin with UV-B (0.5 J/cm2) was found to convert about one-third of endogenous 7-dehydroc!iolestero! (2.3 (xgcnr) into previtamin l);. and another third into the precursor lumisterol and the inactive metabolite tachysterol (Obl-Tabot el «/., 2000). UV-B inactivates some of the newly generated vitamin D and its unstable precursors. Vitamin I) synthesis rapidly becomes maximal upon continued exposure, because light-induced production and destruction of vitamin D reach an equilibrium. It has been estimated that exposure of the entire body to summer sun for less than 20 minutes is sufficient to generate v itamin D in skin equivalent to an oral dose of 250 pg or more (Vieth. 1999).

Skin pigmentation decreases the effective light dose and greatly decreases \ itamin D production with less than maximal sun exposure (Kreiter ei til.. 2000).

The diminished vitamin D production in older people (75% decline bv age 70) has been attributed in part to a lower concentration of'unestenlied 7-dehvdrocliolesterol in skin (Holick, 1999).

Dietary sources

Most natural vitamin D is consumed in the form of vitamin D3 {D3, cholecalciferol). The content of foods is expressed in (ig or International Units (1 )ig - 401U), The only

Figure 9.13 Light-induced synthesis iifvit.imin Dj

natural foods that contain the structurally related \ itamin D: |D2. ergocalciferoll are mushrooms. Ocean lisli is the main dietary source of D3. Particularly rich sources are the fatty types of tisli. such as salmon (O.l 0.3 ng/g>, sardines (0.4 p,g/g), and mackerel {O.I M-gg). Lean ocean lish. such as cod (O.OI jxg.'g). and freshwater fish, contain only little vitamin D.

Most milk in the US is fortified at a level of 5 jxg'L Considerable variation of actual milk vitamin D content have been observed in the past, however 11 lolick et al.. 1}. Other dairy products, such as yoghurt or cheese, are not usually fortified. D2. which is the compound originally used for fortification, has been replaced with 03 in the US and many other countries. Vitamin l): can be produced relatively simply by UV light irradiation of lanosterol. 02 is biologically less active than 03 (Trang et al„ 1998).

Typical daily vitamin D intakes in North American women may be as low as 2.5 (ig (Krall el al.. 1989). and usually insufficient to prevent suboptimal vitamin D status in regions with low sunlight exposure (Vieth, Cole et al., 2001). In Denmark, where milk does not contain added vitamin D. median daily intakes around 3 fig in men, and around 2 in women were recorded (Osier et al., 1998), Even lower median intakes (1.2 fig d) were reported for Australians (Pasco el al„ 2001). Older people in particular, who need much more vitamin D (at least 10 jig for ages 51 70, and 15 fig for people over 70) than younger people, commonly do not get enough (Kohltneier et al., 1997).

Digestion and absorption

Vitamin D is highly fat-soluble and becomes part of mixed micelles (consisting mainly of bile acids, phospholipids, fatty acids and monoglycerides) during fat digestion. Nearly all of the ingested vitamin D is absorbed. The vitamin enters the small intestinal

membrane membrane

Figure 9.14 Intestinal absorption of «itamin D

membrane membrane

Figure 9.14 Intestinal absorption of «itamin D

cell along with fatty acids and other lipids in an incompletely understood process. Chylomicrons then carry vitamin D into lymph vessels and eventually into blood circulation. 1 ittle, if any, vitamin I) is released white the chylomicrons circulate and rapidly lose niosl of their triglyceride load. The liver takes up about half of the triglyceride-depletcd chylomicrons through a receptor-mediated process that involves apolipoprotcin F and the I DL receptor. Bone marrow and bone take up about 20%, and other extra-hepatic tissues clear the remainder. Vitamin D reaching the liver can be secreted again into circulation as a complex with vitamin D-binding protein (DBP, group-specific component. Gc).

Transport and cellular uptake

Blood circulation: Vitamin D and all its normal metabolites in blood are bound to DBP. Almost all of the vitamin D in circulation is 25-hydroxy-vitamin D (25-D); much smaller amounts are 1.25-dihydroxy-vitamin D (1.25-D). Typical 25-D concentrations in plasma of young adults living under sun-rich conditions are well in excess of lOOnmol/1 (Vieth. 1999). Nonetheless, the lower limit of reference ranges is commonly set to 50 nmol I or lower. Average 25-D concentrations of people living at latitudes of 50 or higher may be as low as 40 nmol I during the w inter months (Trang ei ul., 199S). Typical 1,25-D concentrations m vitamin D-replete people tend to he around lOOpmol 1. 25-D concentrations are low in vitamin D-dclicient people, intermediate with adequate status, and increase further with excessive dietary intakes (but not with very intense UV light exposure). 1,25-D concentrations also are km in vitamin D deficiency, but do not increase further after adequate vitamin D intakes are exceeded. Thus, 25-D concentration in plasma is a good marker to reflect both inadequate and excessive vitamin D supplies.

It has been the traditional view that because of their high fat solubility vitamin metabolites can cross plasma membranes by simple diffusion. A more directed entry pathway may pertain in some tissues, however, such as cndocytolic uptake mediated by cubilin and or mcgalin (LDL-receptor related protein 2, LRP2). Blood bram barrier Transport of vitamin D metabolites from blood into brain is very limited (Pardridge el a!.. 11>XS). The underlying mechanisms are not well understood. Materno-fetal transfer 25-D is the main metabolite supplied by the mother to the fetus through incompletely understood mechanisms (Salle et at., 2000). Fetal concentrations arc lower than on the maternal side. Vitamin D is not only transferred to the fetus, but also has important functions in the placenta itself. It is no surprise, therefore, that placenta expresses the vitamin D activating enzyme 25-hydroxy-vitamin D(3>-1 «■-hydroxylase (Zchnder el at.. 2001).

Metabolism

Vitamin D is metabolized extensively in liver, intestines, and kidneys More recent evidence shows that keratinocytes in skin are fully autonomous in respect to \ itamin D metabolism and are capable of all major activating and inactivating reactions (Scbuessler el at.. 20011, Similarly, osteoblasts, parathyroid cells, myelocytes and other cell types have relevant metabolic activity. Three best-recognized enzyme reactions produce two biologically active metabolites. l«.25-dihydroxy-vitamin D and 24R.25-dihvdro\y-vitamin D (Norman, 20011.

Microsomal vitamin D(3) 25-hydroxylase (CYP2D25, identical with sterol-27 hydroxylase. CYP27A) in liver and intestines catalyzes the essential first step in the bioactivation of the prohormone vitamin D (Theodoropoutos et a!.. 2001). This reaction is so effective upon lirst pass of newly absorbed \ itamiit D through small intestine and liver, that blood contains very little unmetabolized vitamin L>.

Activation to Itr,25-d¡hydroxy-vitamin D 11,25-D) is completed in proximal tubular epithelial cells of the kidneys by calcidiol 1-monooxygenase (25-hydroxy-\ itamin D-l«-hydroxylase. CYP27B1, P450CI-Ö. ECl. 14.13.13), a mitochondrial cytochrome P450

K,0
1 <1.25-Dlftydtoxy-vitomin 0,

red.lerredoxin ox.farrodoxi«

lad terredoxin*

red.lerredoxin ox.farrodoxi«

CYP 7

' radfi

■CH.CVP24r°r lad terredoxin*

1ir.23S.25- Tnnydfoxy-vttanun D,

Vox lorrodoxtn

1u.24ft.25 It (hydroxy-vitamin D,

1n.25D*hy(lrt»y aa-oxo-vilamm D, tir.23S.25-TnhytJroxy 24 0XO-vitamin D}

Vox lorrodoxtn

1u.24ft.25 It (hydroxy-vitamin D,

red lerredoxm

1ir.23S.25- Tnnydfoxy-vttanun D,

C-24 oxidation pathway

C-23 ojxsation pathway

C-24 oxidation pathway

CYP24

red lerredoxm vox forredoxin

»HO« Cj Iragmenl oxidj/od NAOPH terredoxinN /

[NAOPH loredoxin A reductase (FAD) reduced / V tenetiox.ri NADP

ÇOH red.torrodowin ox lornedo»: 1 <i. 25 ■ Trihydt oxy-24 -oxo-] ) T °i W * H-'?

vilamin d., qyp 7

COOH

Figure l.lfi CatJbold pathways Tar l(i,2')R,2S tnhydroxy-vitJmin H, oxidase. Ferrcdoxin, which provides the reducing equivalents for all cytochrome P450 systems, is regenerated by ferredoxin-NADP reductase (EC 1.18.1.2. FAD-containing).

Before ihi> hydroxy! at ion can take place, however, the 25-D precursor has to reach the tubular cell. The main, and possibly exclusive route is glomerular filtration of the 25-D/DBP complex and endocytosis mediated jointly by cubit in and mega! in (Nvkjaer i-t u!., 2001). Decreased filtration rate las with advancing age or in renal failure) or defective cubilin or megalin diminish the production of 1,25-1). Some 25-D hydroxy lut ion also occurs in extrarenal cells including skin and white blood cells tl tew ison el at., 2000; Schuessler et at,, 2001). The glomerular filtration rate of a healthy man can be expected to fall from about 140 ml. minute at age 20 to about 40 ml minute by age 70 il .indeman. 1999). This age-typical decline m renal function raises the threshold plasma 25-D concentration that sustains adequate 1,25-D production by more than half. A several-fold

25-Dihydioxy-vitamin D3

25-Dihydioxy-vitamin D3

f IWTWtoKin \S

' ¥ NADPH'tefrodoxm

CYP24

f IWTWtoKin \S

' ¥ NADPH'tefrodoxm

24 H 25-Dihydroi(y vitamin D;i

24 H 25-Dihydroi(y vitamin D;i

C24 oxidation pathway

Figur» 9.17 Catabolism of 25-hydro*y-vitamin D

incrcatsc in dietary intakes or endogenous production is necessary to make up for this difference (Victh. 1999). Current recommendations recognize that people over 70 years of age need three times more vitamin D than young adults (Institute of Medicine. 1997), Another mitochondrial cytochrome P450 oxidase, 25-hydroxy-vitamin D-24R-hydroxytase (CYP24) converts 1,25-D into I a ,24 R^25-tri hydros v-v i tamin I) (24.25-Dt. Alternatively, hydroxylation at carbon 23 may occur. Irreversible 3-epoxidation initiates a distinct metabolic pathway. Hydroxylations of the side chain, possibly with the involvement ofCYP24 (Inouyeand Sakaki, 2(H) I), generate the water-soluble metabolite calcitroic acid (l(u-hydroxy-24.25.26.27-tetr:inor-23-carboxyl-vitamin D).

The bulk of 25-D is catabolized through the C24 oxidation pathway with 24R, 25-dihydroxy-vitamin D, as an important intermediate metabolite (I lenry, 20(11), which may have its own specific biological activities.

Numerous additional hvdroxylated and otherwise modified metabolites are present in blood and tissues. While it has been held that calcitroic acid and other metabolites

Figure 9.18 Metabolite* derived from vitamin Or J-epi-intermediar«

are inactive, more recent investigations seem to indicate that they retain some typical vitamin D activity (Harant et ai, 2000).

Storage

Vitamin I) is known to be stored extensively in the liver. These stores sustain normal vitamin D-dependent functions during the winter at high latitudes even in the absence of signilicant dietary intakes. However, quantitative data on amounts stored, alternative storage sites, or the precise mechanisms for deposition and release, are not available.

Smaller amounts of vitamin 1) are stored in cxtrahepatic tissues. The cartilage oligomeric matrix protein may provide a local storage mechanism that supports rapid delivery to nearby target structures (Quo et ul., IWX|.

Excretion

Calcitroic acid the 3- and 24-glucuronides of 24.25-1). and additional v itamin D metabolites are excreted with bile. Since intestinal absorption of vitamin I) is very efficient, losses of active vitamin D v ia this route are likely to be minor. Quantitative information in this regard is limited however.

25-1) tn plasma is bound to DBP (group-specific component. Ge), a single peptide chain with molecular weight of 52 000 (Witke tHal., 1993). A small percentage of this complex is filtered in the renal glomeruli. DBP binds with high affinity tocubilin at the brush border membrane ofthc proximal renal tubule, as described above. Megalin assists with the endocytosis and intracellular trafficking of cubilin and all its captured ligands (which include retinol-binding protein and transferrin among others). Due to the high efficiency ofthc process very little of the liltcrcd vitamin D escapes with urine. Calcitroic acid is a major caiabolitc of both vitamin D: and D; in urine (Zimmerman et ul.. 2001).

Regulation

Feedback inhibition strongly limits 1,25-D production (Norman, 2001). The main activator of renal production of 1,25-D is PT1I, which increases expression of 1 «-hydroxylase (Theodoropoulos et ul.. 2001), Calcitonin, estrogen, prolactin, insulin, growth hormone, and glucocorticoids also activate this key enzyme.

calcitonin estrogen prolactin insulin

growth hormone glucocorticoids

25-hydroxy-vitamtn 0

1/.,25-dihydro*y-vitamin D

1/.,25-dihydro*y-vitamin D

Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

Get My Free Ebook


Post a comment