Derived from either ergosterol (Vitamin D2 found in plants and commercially derived from the fungus ergot) or 7-dehydrocholesterol (found in stratum Malphigi, intermediate in minor pathway of synthesis of cholesterol) by the action of ultraviolet light. 7-dehydrocholesterol – (in the skin) -> secosterol (cis) – (isomerase) -> (trans) cholecalciferol (Vitamin D3). Since it involves action of sunlight in its metabolism so Vitamin D is also called the sunshine vitamin.
Ac ti va t io n o f Vi ta mi n D Vitamins D2 and D3 are prohormones, but are converted
in vivo to
the active form of Vit D by two
sequential hydroxylation reactions.
In the liver, hydroxylation occurs at the 25 position (25-HCC is forced) catalysed by a specific hydrolate which requires molecular oxygen, cyt P-450 and NADPH.
25-HCC is the predominant form of Vit D in the plasma and the major storage form. In the plasma, 25-HCC is bound to Vitamin D binding protein (VDBP), an alpha-2 globulin.
In the kidney, it is further hydroxylated by a specific alpha-1 hydroxylase located in the mitochondria of PCT and which requires O2, cyt P-450, NADPH and ferrodoxin. Thus, 1,25rd
dihydroxy cholecalciferol (DHCC) is generated. Since it contains another OH at 3 position it is also called calcitrol and is the active form of the vitamin. It is a hormone.
Regulation of formation of DHCC (calcitriol): o
+ low plasma phosphate
+ low Ca, which triggers PTH (+)
- DHCC (*effect on 1-hydroxylase)
Ac ti on s o f Vi ta mi n D 1. Calcemic actions a.
In the intestine: promotes the absorption of calcium and phosphorus (binds to a nuclear receptor – VDR which binds to VDRE upon forming a dimer with RXR which codes for calbindin, which binds to calcium and is actively pumped from the inner surface of the villous cells into the blood)
b. On the bone: Mineralization of the bone by increasing the activity of osteoblasts . Osteoblasts also secrete a cytokine RANKL which promotes osteoclastic bone resorption and alkaline phosphatase activity to provide a dequate calcium and phosphorus. Vit D also promotes increased production of bone matrix proteins c.
On Renal Tubules: Increases reabsorption of calcium and phosphorus by renal tubules (PTH only conserves calcium).
2. Extracalcemic actions a.
Modulates immune system, haemopoiesis
b. Reduces risk for cancer and coronary vascular disease
Distribution and requirement Exposure to sunlight produces cholecalciferol. So at least 15 minutes of exposure without sunscreen is recommended. Fatty fish, liver and egg yolk are good sources of the vitamin. Milk, unless fortified, is not a good source. RDA: 5-10 micrograms (200 IU) per day in adults. Double in pregnancy and in children. Triple in elderly people.
Clinical indications 1. Nutritional rickets: Deficiency of Vitamin D causes a net demineralization of the bone, resulting in rickets in children and osteomalacia in adults. a.
Rickets is characterized by continued formation of collagen matrix of the bone, but incomplete mineralization resulting in soft, pliable bones. Weight bearing bones are bent (bow-legs, knock-knee, rickety rosary i.e. enlargement of epiphysis at the lower end of the ribs and costochondral junction, and pigeon chest).
b. In osteomalacia, demineralization and osteoporosis of pre-existing bones increases their susceptibility to fracture. c.
Vitamin D deficiency never produces severe hypocalcemia/tetany (PTH takes over).
2. Renal rickets: This disorder results from chronic renal failure and thus, decreased ability to form DHCC. DHCC administration is effective replacement therapy. 3. Classic rickets may also be produced by low exposure to sunlight / malabsorption of vitamin due to obstructive jaundice and steatorrhoea. 4. Fanconi syndrome / Vit D resistant rickets 5. Hypophosphatemic rickets results from defective renal tubular reabsorption of phosphate.
Toxicity of Vitamin D Vitamin D is the most toxic of all vitamins. Doses above 10,000 units per day for long periods can cause loss of appetite, intense thirst, nausea, hypertension, difficulty in speaking and stupor. Excessive exposure to sunlight does not produce toxicity because excess D3 is destroyed by the sun itself.