افتح القائمة الرئيسية

ڤيتامين د

فيتامين دي Vitamin D،هو منظّم الجسم الأساسي لتوازن الكالسيوم. يساعد على تزويد العظم بالمعادن وتطوير الهيكل العظمي. يعتبر مؤشر هورموني، وليس له ذاته أي نشاط هورموني، مع أنه من المكن أن يتم تحويله إلى جزيئة ذات نشاط هورموني.

ڤيتامين د
صف عقاقير
Cholecalciferol-3d.png
مميزات الصف
الاستخدامRickets, osteoporosis, vitamin D deficiency
كود ATCA11CC
الهدف الحيويvitamin D receptor
البيانات الإكلينيكية
Drugs.comMedFacts Natural Products
الوصلات الخارجية
MeSHD014807

تتضمن كلمة فيتامين د عددا من 1 حتى 5 وهي مواد ثابتة حرارياً ومن أهم هذه الفيتامينات فيتامين د2 المسمى إرجوكالسيفيرول وينتج بتأثير الاشعة فوق البنفسجية على الستيرول النباتي والاخر فيتامين د3 والمسمى كوليكالسيفيرول: وهو المركب الطبيعي المضاد للكساح وينتج بتاثير الاشعاع على فيتامين أولي أو بروفيتامين dehydrocholestrol-7 الموجود في الجلد.

The major natural source of the vitamin is synthesis of cholecalciferol in the lower layers of skin epidermis through a chemical reaction that is dependent on sun exposure (specifically UVB radiation).[1][2] Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements.[3][4][5] Only a few foods, such as the flesh of fatty fish, naturally contain significant amounts of vitamin D.[6][7] In the U.S. and other countries, cow's milk and plant-derived milk substitutes are fortified with vitamin D, as are many breakfast cereals. Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D.[6] Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.[6]

Vitamin D from the diet, or from skin synthesis, is biologically inactive. A protein enzyme must hydroxylate it to convert it to the active form. This is done in the liver and in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals if exposed to sufficient sunlight, it is not essential, so technically not a vitamin.[5] Instead it can be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations.[5]

Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status.[8][9] Calcifediol is further hydroxylated by the kidneys to form calcitriol (also known as 1,25-dihydroxycholecalciferol), the biologically active form of vitamin D.[10] Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.[6]

Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia).[11] Vitamin D supplements are given to treat or to prevent osteomalacia and rickets. The evidence for other health effects of vitamin D supplementation in the general population is inconsistent.[12][13] The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people,[14] and another concluding no clear justification exists for recommending supplementation for preventing many diseases, and that further research of similar design is not needed in these areas.[15]

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فهرست

الأنواع

الاسم التركيب الكيميائي البنية
ڤيتامين د1 Mixture of molecular compounds of ergocalciferol with lumisterol, 1:1
ڤيتامين د2 ergocalciferol (made from ergosterol)  
ڤيتامين د3 cholecalciferol (made from 7-dehydrocholesterol in the skin).  
ڤيتامين د4 22-dihydroergocalciferol  
ڤيتامين د5 sitocalciferol (made from 7-dehydrositosterol)  

Several forms (vitamers) of vitamin D exist. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol; vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol.[16] Vitamin D2 was chemically characterized in 1931. In 1935, the chemical structure of vitamin D3 was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.[17]

Chemically, the various forms of vitamin D are secosteroids, i.e., steroids in which one of the bonds in the steroid rings is broken.[17] The structural difference between vitamin D2 and vitamin D3 is the side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.


إمتصاصه

يمتص فيتامين د في النصف الأعلى من الامعاء الدقيقة في وجود املاح الصفراء وكذلك يرتبط بالالفا -جلوبيولين في البلازما. من أهم مناطق تخزين الفيتامين في الجسم: العضلات والنسيج الدهني.

استعمالاته

يساعد فيتامين دي في: تشكيل خلايا الدم، المناعة، تمايز الخلايا الأمرالذي قد يقلل من أخطار السرطان. أظهر فيتامين دي قدرته على توفير الحماية من أمراض المناعة كالتهاب المفاصل المناعي، تصلّب الأنسجة المتعدّد، وسكّري الأطفال.

يساعد فيتامين دي الجسم على الحفاظ على مستويات الأنسولين الضرورية في الدم. توجد مستقبلات فيتامين دي في البنكرياس، حيث يتم إنتاج الأنسيولين. كبسولات البدائل قد تزيد من إفراز الإنسولين في الأشخاص المصابين بالسكّري النوع 2.

فيتامين دي يستعمل في الحالات التالية:

إن المدى الذي يساهم به فيتامين دي للمساعدة على تخفيض الكسور وخسارة العظم لدى المسنين ما زال غير مؤكّدا، على أية حال بعض الدراسات تشير إلى أنه مفيد في هذه الحالات.

أبحاث متقدمة تشير إلى إمكانية استعمال فيتامين دي أيضا للمساعدة في الكآبة الموسميّة، الطرش القوقعي الثنائي، مقاومة زيادة النوبات، وتساعد بتصلّب الأنسجة المتعدّد ومتلازمة الجيب المريضة.

 
تركيب فيتامين دي

الكيمياء الحيوية

انتاجه في الجلد

عند التعرض للشمس يتحول دي هيدرو كوليسترول بوجود الأشعة فوق البنفسجية إلى فيتامين د.

 
The epidermal strata of the skin. Production is greatest in the stratum basale (colored red in the illustration) and stratum spinosum (colored orange).

ڤيتامين دي كڤيتامين

Since Vitamin D is naturally produced by human body it only became a Vitamin because of cultural changes, related to civilization that reduced natural production due to less exposure of the human skin to the sun, caused by the use of more clothes and less time of outdoors exposition.[18]


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آلية التخليق (form 3)

1. Vitamin D3 is synthesized from 7-dehydrocholesterol, a derivative of cholesterol, which is then photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is pre-vitamin D3.  
2. Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a antarafacial hydride [1,7]Sigmatropic shift.  
3. Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes, and stored until it is needed.

25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D3 or calcitriol) and 24R,25(OH)2D3. This conversion occurs in a tightly regulated fashion.

Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end).
 

آلية العمل

التغذية

 
Milk and cereal grains are often fortified with vitamin D.

The Canadian Pediatric Society recommends 2,000 IU daily for pregnant and breastfeeding women.[19]

في الطعام

يوجد في السمك, البيض, الحليب. Natural sources of vitamin D include:[20]

  • Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU (one IU equals 25 ng)
  • Fatty fish species, such as:
    • Herring, 85g (3 oz) provides 1383 IU
    • Catfish, 85g (3 oz) provides 425 IU
    • Salmon, cooked, 3.5 oz provides 360 IU
    • Mackerel, cooked, 3.5 oz, 345 IU
    • Sardines, canned in oil, drained, 1.75 oz, 250 IU
    • Tuna, canned in oil, 3 oz, 200 IU
    • Eel, cooked, 3.5 oz, 200 IU
  • One whole egg, 20 IU

نقص فيتامين دي

 
Calcitriol (1,25-dihydroxycholecalciferol). Active form. Note extra OH groups at upper right and lower right.

نقص فيتامين دي في الأطفال قد يسبّب،الكساح (Rickets) والتي تتميز باضطراب في تكوين العظام نابعا من نقص الكالسيوم والفسفور في النهايات الغضروفية للعظام.كذلك يسبب نقص هذا الفيتامين في البالغين لين وترقق عظام (osteomalacia) هذه الحالة تعالج عادة بمعوِّضات الكالسيوم وفيتامين دي. إن ترقق العظام يجب أن يشخّص ويعالج من قبل طبيب مختص. قد تحدث تشكيلات عظمية شاذّة في أولئك المصابين بنقص فيتامين دي. يكون النقص أكثر شيوعا في الشتاء حيث الحصول على نور الشمس صعب. حالات نقص فيتامين دي شائعة أيضا في المناطق الملوّثة جدا، حيث يمكن أن تُحجب الأشعة فوق البنفسجية.

النباتيون الصارمون، مدمنو الخمور، أولئك المصابون بأمراض الكبد أو الكلية، والأشخاص ذو البشرة السمراء، معرضون أكثر لنقص فيتامين دي. المصابون بأمراض الكبد أو الكلية ينتجون فيتامين دي لكن لا ينشّطونه.

الأفرادالذين يعانون من سوء الامتصاص المعوي عموما لديهم نقص فيتامين دي. أولئك الذين تكون وظيفة البنكرياس عندهم غير كافية، مثل حالات التليف الكيسي أو التهاب البنكرياس، أو مصابون بفرط الدرقية، في أغلب الأحيان لديهم نقص فيتامين دي.


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دوره في العلاج والوقاية من السرطان

يقول علماء ان استخدام جرعات كبيرة من فيتامين دي يمكن أن تخفض الى النصف مخاطر التعرض للاصابة بالسرطان. وقام باحثون بمراجعة 63 دراسة قديمة وخلصوا الى أن فيتامين دي يمكن ان يخفض مخاطر تطور سرطان الثدي والمبايض والقولون وانواع اخرى من السرطان.

وقد أجريت هذه الدراسات ونشرت ما بين أعوام 1966 و2004 ، وهي تشمل 30 دراسة بحثية حول سرطان القولون و13 حول سرطان الثدي، و26 حول سرطان البروستاتا و7 حول سرطان المبايض.

وقال الباحثون على الاثر أن التحليلات تشير الى انه في انواع معينة من السرطان فانه لا يمكن تجاهل دور فيتامين دي.

ترحيب حذر

رحبت الجمعيات الخيرية بحذر بالدراسة التي أجرتها جامعة كاليفورينا، الا انها نبهت إلى أن الإفراط في استخدام فيتامين دي يمكن أن يلحق أضرارا بالكلى والكبد.

وينتج الشكل الطبيعي من "فيتامين دي" من الجلد عقب التعرض لاشعة الشمس ويطلق عليه "دي -3"، ويمكن الحصول على الفيتامين ايضا من بعض الاطعمة مثل الاسماك الغنية بالزيت واللحوم. ورصدت الدراسة التي اجريت في جامعة كاليفورينا بسان دييغو العلاقة بين تناول"فيتامين دي" وانخفاض معدلات الاصابة بالسرطان.

وفي هذا السياق اشارت الدراسة الى تزايد معدلات الاصابة بالسرطان بين الافارقة والكاريبيين مقابل انخفاضها لدى البيض ، ربما بسبب ان البشرة السوداء لا تنتج كمية كافية من"فيتامين دي".

ويقول العلماء ان تناول 25 ميلجرام من "فيتامين دي" يوميا يمكن ان يقلل خطر الاصابة بسرطان القولون بنسبة 50 بالمئة وخطرة الاصابة بسرطان الثدى والمبايض بنسبة 30 بالمئة. إلا ان العلماء اقروا بأن تناول كميات اكبر من "فيتامين دي" هو امر يجب التعامل معه بحذر.

يقول العلماء ان تناول خمسين ميلجرام من "فيتامين دي"قد يؤدي إلى أن الجسم قد يمتص كمية كبيرة من الكالسيون وهو امر قد يتسبب في الاضرار بالكبد والكلى.

ويرى البروفيسور سيدريك جارلاند الذي ترأس فريق البحث أنه تبين أن هناك حاجة لايلاء "فيتامين دي" عناية أكبر.

ويعتبر جارلاند أنه في حال عدم وجود أشعة شمس كافية، فانه يمكن الحصول على الفيتامين من مصادر أخرى، غير أنه اشار أيضا إلى أن التعرض للشمس له محاذير اخرى.

ويضيف على ذوي البشرة الداكنة التعرض بشكل أكبر لاشعة الشمس من اجل الحصول على كمية كافية من "فيتامين دي.

لا أدلة

بيد ان البروفيسور كولين كووبر من معهد ابحاث السرطان فيقول ان هناك حاجة لاجراء المزيد من الابحاث للحصول على ادلة مؤكدة بشأن فوائد "فيتامين دي". ويقول كووبر ان الدراسة اخفقت في تقديم أي آلية بشان الكمية المطلوبة من فيتامين دي التي تقي من السرطان. [21]

سرطان البروستاتا

 
فيتامين دي وسرطان البروستاتا

في محاولة جديدة وجادة لعلاج أكثر أنواع السرطانات الذكورية شيوعا في العالم ، نجح باحثون أمريكيون في تطوير أقراص بفيتامين " د " لمعالجة المصابين بسرطان البروستاتا في حالة متقدمة. وقد تمكنت شركة صناعة الأدوية بالولايات المتحدة "نوفاسيا" من تصنيع حبوب دواء تحتوي على هذا الفيتامين بصورة مركزة، دون مخاطر الأعراض الجانبية المترتبة عن جرعة مُفرطة .

ومن المتوقع أن يكون العقار "Asentar DN-101" متوفرا قبل عام 2009، إذا ما نجحت الاختبارات الطبية ، حيث سيُعطى هذا الدواء للمصابين الذين بلغوا مرحلة متقدمة من المرض، بالإضافة إلى العلاج الكيميائي.

أوضح أحد الباحثين بجامعة بيرمنجهام، أن العقار أدى إلى نتائج مثيرة في المراحل الأولى من اختبارين طبيين ، مؤكدا أن الذين تناولوا هذا الدواء ارتفع معدل أمل الحياة لديهم بحوالي تسعة أشهر، مقارنة مع مرضى آخرين لم يتناولوا سوى عقار العلاج الكيماوي تاكسوتير.

وينتظر أن يُنصح المصابون بتناول قرص واحد كل أسبوع، إلى جانب تتبع نظام التاكسوتير الأسبوعي الذي يمتد على ثلاثة أسابيع من أصل أربعة.

جدير بالذكر أن سرطان البروستاتا ينتشر في المناطق البعيدة عن خط الاستواء، بسبب قلة ضوء الشمس. [22]

الجرعة الموصّى بها

فيتامين دي الذي يكون على شكل مكملات (كبسولات) يمكن الحصول عليه كفيتامين دي 2 -إرجوكالسيفيرول أو كفيتامين دي 3 -كوليكالسيفيرول. تحتوي الكبسولات متعددة الفيتامين في العادة على جرعة فيتامين دي الموصّى بها عموما 200-400 آي يو (وحدة دولية)، أو 5-10 ميكروغرام، كلّ يوم. 400 آي يو توجد في حبوب فيتامينات ما قبل وبعد الولادة.

المسنون والمصابون بمتلازمات سوء الامتصاص، والفشل الكبدي، ومتلازمة الالتهاب الكلوي، يأخذون مكملات تحوي على 50,000 آي يو، أو 1,250 ميكروجرام، إسبوعيا لفترة ثمانية أسبابيع. هذه العلاجات يجب أن ترتّب تحت إشراف الطبيب.

Dietary intake

Recommended levels

الولايات المتحدة
المجموعة العمرية RDA (IU/day) (μg/day)[23]
رضع 0–6 شهر 400* 10
رضع 6–12 شهر 400* 10
1–70 سنة 600 15
71+ سنة 800 20
حامل/مرضعة 600 15
المجموعة العمرية Tolerable upper intake level (IU/day) (µg/day)
رضع 0–6 months 1,000 25
Infants 6–12 months 1,500 37.5
1–3 years 2,500 62.5
4–8 years 3,000 75
9+ years 4,000 100
Pregnant/lactating 4,000 100 [23]
كندا
المجموعة العمرية RDA (IU) Tolerable upper intake (IU)[24]
Infants 0–6 months 400* 1,000
Infants 7–12 months 400* 1,500
Children 1–3 years 600 2,500
Children 4–8 years 600 3,000
Children and Adults 9–70 years 600 4,000
Adults > 70 years 800 4,000
Pregnancy & Lactation 600 4,000
أستراليا ونيوزيلندا
المجموعة العمرية Adequate Intake (μg) Upper Level of Intake (μg)[25]
Infants 0–12 months 5* 25
Children 1–18 years 5* 80
Adults 19–50 years 5* 80
Adults 51–70 years 10* 80
Adults > 70 years 15* 80
السلطة الأوروپية لسلامة الغذاء
المجموعة العمرية Adequate Intake (μg)[26] Tolerable upper limit (μg)[27]
Infants 0–12 months 10 25
Children 1–10 years 15 50
Children 11–17 years 15 100
Adults 15 100
Pregnancy & Lactation 15 100
* Adequate intake, no RDA/RDI yet established

Conversion: 1 µg = 40 IU.

Sources

Although vitamin D is not present naturally in most foods,[3][5] it is commonly added as a fortification in manufactured foods. In some countries, staple foods are artificially fortified with vitamin D.[28]

Natural sources

In general, vitamin D2 is found in fungi and vitamin D3 is found in animals.[29][30] Vitamin D2 is produced by ultraviolet irradiation of ergosterol found in many fungi. The vitamin D2 content in mushrooms and Cladina arbuscula, a lichen, increase with exposure to ultraviolet light.[31][32] This process is emulated by industrial ultraviolet lamps, concentrating vitamin D2 levels to higher levels.[30]

The United States Department of Agriculture reports D2 and D3 content combined in one value.

Fungal sources
Source  μg/g IU/g
C. arbuscula (lichen), thalli, dry[31] vitamin D3 0.67–2.04 27–82
vitamin D2 0.22–0.55 8.8–22
Agaricus bisporus (common mushroom): D2 + D3
Portobello Raw 0.003 0.1
Exposed to ultraviolet light 0.112 4.46
Crimini Raw 0.001 0.03
Exposed to ultraviolet light 0.319 12.76
Animal sources[33]
Source IU/g Irregular
Cooked egg yolk 0.7 44 IU for a 61g egg
Beef liver, cooked, braised 0.5
Fish liver oils, such as cod liver oil 100 450 IU per teaspoon (4.5 g)
Fatty fish species
Salmon, pink, cooked, dry heat 5.2
Mackerel, Pacific and jack, mixed species, cooked, dry heat 4.6
Tuna, canned in oil 2.7
Sardines, canned in oil, drained 1.9

السبيل التفاعلي

انقر على الأيقونة في الركن الأسفل الأيمن للفتح. Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Vitamin D Synthesis Pathway (view / edit)
  1. ^ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Photochemistry

 
The photochemistry of vitamin D biosynthesis in animal and fungi
 
Thermal isomerization of previtamin D3 to vitamin D3

The transformation that converts 7-dehydrocholesterol to vitamin D3 occurs in two steps.[34][35] First, 7-dehydrocholesterol is photolyzed by ultraviolet light in a 6-electron conrotatory ring-opening electrocyclic reaction; the product is previtamin D3. Second, previtamin D3 spontaneously isomerizes to vitamin D3 (cholecalciferol) in an antarafacial sigmatropic [1,7] hydride shift. At room temperature, the transformation of previtamin D3 to vitamin D3 in an organic solvent takes about 12 days to complete. The conversion of previtamin D3 to vitamin D3 in the skin is about 10 times faster than in an organic solvent.[36]

The conversion from ergosterol to vitamin D2 follows a similar procedure, forming previtamin D2 by photolysis, which isomerizes to vitamin D2.[37] The transformation of previtamin D2 to vitamin D2 in methanol has a rate comparable to that of previtamin D3. The process is faster in white button mushrooms.[30](fig. 3)

Evolution

Vitamin D can be synthesized only by a photochemical process. Phytoplankton in the ocean (such as coccolithophore and Emiliania huxleyi) have been photosynthesizing vitamin D for more than 500 million years. Primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D.

Land vertebrates required another source of vitamin D other than plants for their calcified skeletons. They had to either ingest it or be exposed to sunlight to photosynthesize it in their skin.[29][36] Land vertebrates have been photosynthesizing vitamin D for more than 350 million years.[38]

In birds and fur-bearing mammals, fur or feathers block UV rays from reaching the skin. Instead, vitamin D is created from oily secretions of the skin deposited onto the feathers or fur, and is obtained orally during grooming.[39] However, some animals, such as the naked mole-rat, are naturally cholecalciferol-deficient, as serum 25-OH vitamin D levels are undetectable.[40]

Industrial synthesis

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.[41] The 7-dehydrocholesterol is a natural substance in fish organs, especially the liver,[42] or in wool grease (lanolin) from sheep. Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.[41][30]

Mechanism of action

Metabolic activation

 
Liver hydroxylation of cholecalciferol to calcifediol
 
Kidney hydroxylation of calcifediol to calcitriol

Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcifediol. Circulating calcifediol may then be converted into calcitriol, the biologically active form of vitamin D, in the kidneys.[43]

Whether it is made in the skin or ingested, vitamin D is hydroxylated in the liver at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcifediol or 25(OH)D).[44] This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase, the product of the CYP2R1 human gene, and expressed by hepatocytes.[45] Once made, the product is released into the plasma, where it is bound to an α-globulin carrier protein named the vitamin D-binding protein.[46]

Calcifediol is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-α position (lower right of the molecule) to form calcitriol (1,25-dihydroxycholecalciferol, 1,25(OH)2D). The conversion of calcifediol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene. The activity of CYP27B1 is increased by parathyroid hormone, and also by low calcium or phosphate.[5][43]

Following the final converting step in the kidney, calcitriol is released into the circulation. By binding to vitamin D-binding protein, calcitriol is transported throughout the body, including to the classical target organs of intestine, kidney and bone.[17] Calcitriol is the most potent natural ligand of the vitamin D receptor, which mediates most of the physiological actions of vitamin D.[5][43]

In addition to the kidneys, calcitriol is also synthesized by certain other cells including monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, modulating body defenses against microbial invaders by stimulating the innate immune system.[43]

Inactivation

The activity of calcifediol and calcitriol can be reduced by hydroxylation at position 24 by vitamin D3 24-hydroxylase, forming secalciferol and calcitetrol, respectively.[44]

Difference between substrates

Vitamin D2 (ergocalciferol) and vitamin D3 (cholecaliferol) share a similar mechanism of action as outlined above.[44] Metabolites produced by vitamin D2 are sometimes named with an er- or ergo prefix to differentiate them from the D3-based counterparts.[47]

  • Metabolites produced from vitamin D2 tend to bind less well to the vitamin D-binding protein.
  • Vitamin D3 can alternatively be hydroxylated to calcifediol by sterol 27-hydroxylase (CYP27A1), but vitamin D2 cannot.
  • Ergocalciferol can be directly hydroxylated at position 24. This hydroxylation also leads to a greater degree of inactivation: while calcitriol's activity decreases to 60% of original after 24-hydroxylation,[48] ercalcitriol suffers a 10-fold decrease in activity on conversion to ercalcitetrol.[49]

التاريخ

American researchers Elmer McCollum and Marguerite Davis in 1914[11] discovered a substance in cod liver oil which later was called "vitamin A". British doctor Edward Mellanby noticed dogs that were fed cod liver oil did not develop rickets and concluded vitamin A, or a closely associated factor, could prevent the disease. In 1922, Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed.[11] The modified oil cured the sick dogs, so McCollum concluded the factor in cod liver oil which cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named.[50][51][52] It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.

In 1925,[11] it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced (now known as D3). Alfred Fabian Hess stated: "Light equals vitamin D."[53] Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928 for his work on the constitution of sterols and their connection with vitamins.[54] In 1929, a group at NIMR in Hampstead, London, were working on the structure of vitamin D, which was still unknown, as well as the structure of steroids. A meeting took place with J.B.S. Haldane, J.D. Bernal, and Dorothy Crowfoot to discuss possible structures, which contributed to bringing a team together. X-ray crystallography demonstrated the sterol molecules were flat, not as proposed by the German team led by Windaus. In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance.[55] The informal academic collaboration between the team members Robert Benedict Bourdillon, Otto Rosenheim, Harold King, and Kenneth Callow was very productive and led to the isolation and characterization of vitamin D.[56] At this time, the policy of the Medical Research Council was not to patent discoveries, believing the results of medical research should be open to everybody. In the 1930s, Windaus clarified further the chemical structure of vitamin D.[57]

In 1923, American biochemist Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials.[58] After irradiating rodent food, Steenbock discovered the rodents were cured of rickets. A vitamin D deficiency is a known cause of rickets. Using $300 of his own money, Steenbock patented his invention. His irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.[59]

In 1969, after studying nuclear fragments of intestinal cells, a specific binding protein for vitamin D called the vitamin D receptor was identified by Mark Haussler and Tony Norman.[60] In 1971–72, the further metabolism of vitamin D to active forms was discovered. In the liver, vitamin D was found to be converted to calcifediol. Calcifediol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D.[10] Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. The vitamin D metabolites, calcifediol and calcitriol, were identified by competing teams led by Michael F. Holick in the laboratory of Hector DeLuca and by Tony Norman and colleagues.[61][62][63]

Research

There is considerable research activity looking at effects of vitamin D and its metabolites in animal models, cell systems, gene expression studies, epidemiology and clinical therapeutics. These different types of studies can produce conflicting evidence as to the benefits of interventions with vitamin D.[64] One school of thought contends the human physiology is fine-tuned to an intake of 4,000–12,000 IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80 ng/mL[65] and this is required for optimal health. Proponents of this view, who include some members of the panel that drafted a now-superseded 1997 report on vitamin D from the IOM, contend the IOM's warning about serum concentrations above 50 ng/mL lacks biological plausibility. They suggest, for some people, reducing the risk of preventable disease requires a higher level of vitamin D than that recommended by the IOM.[65][66]

The United States National Institutes of Health Office of Dietary Supplements established a Vitamin D Initiative in 2014 to track current research and provide education to consumers.[67] In their 2016 review, they recognize that a growing body of research suggests that vitamin D might play some role in the prevention and treatment of types 1 and 2 diabetes, glucose intolerance, hypertension, multiple sclerosis, and other medical conditions. They state further: "however, most evidence for these roles comes from in vitro, animal, and epidemiological studies, not the randomized clinical trials considered to be more definitive. Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated".[6]

Some preliminary studies link low vitamin D levels with disease later in life.[68] Evidence as of 2013 is insufficient to determine whether vitamin D affects the risk of cancer.[69] One meta-analysis found a decrease in mortality in elderly people.[14] Another meta-analysis covering over 350,000 people concluded that vitamin D supplementation in unselected community-dwelling individuals does not reduce skeletal (total fracture) or non-skeletal outcomes (myocardial infarction, ischemic heart disease, stroke, cerebrovascular disease, cancer) by more than 15%, and that further research trials with similar design are unlikely to change these conclusions.[15] A 2019 meta-analysis found that there may be an increased risk of stroke when taking both calcium and vitamin D.[70] The role of vitamin D in vascular calcification can possibly be attributed to these findings.[71]

Vitamin D deficiency is widespread in the European population.[72] European research is assessing vitamin D intake levels in association with disease rates and policies of dietary recommendations, food fortification, vitamin D supplementation, and small amounts of sun exposure.[73]

Apart from VDR activation, various alternative mechanisms of action are under study, such as inhibition of signal transduction by hedgehog, a hormone involved in morphogenesis.[74]

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Further reading

External links


قالب:Vitamins

قالب:Vitamin D receptor modulators