Vitamin D

VITAMIN D
The D vitamins are a group of sterols that have a hormone-like function. The active molecule, 1,25-dihydroxycholecalciferol (1,25-diOH-D3), binds to intracellular receptor proteins. The 1,25-diOH-D3-receptor complex interacts with DNA in the nucleus of target cells in a manner similar to that of vitamin A (see Figure 28.20), and either selectively stimulates gene expression or specifically represses gene transcription. The most prominent actions of 1,25-diOH-D3 are to regulate the plasma levels of calcium and phosphorus.
A. Distribution of vitamin D
1. Diet: Ergocalciferol (vitamin D2), found in plants, and cholecalciferol (vitamin D3), found in animal tissues, are sources of pre-formed vitamin D activity (Figure 28.22). Ergocalciferol and cholecalciferol differ chemically only in the presence of an additional double bond and methyl group in the plant sterol.
2. Endogenous vitamin precursor: 7-Dehydrocholeslerol, an intermediate in cholesterol synthesis, is converted to cholecalciferol in the dermis and epidermis of humans exposed to sunlight. Preformed vitamin D is a dietary requirement only in individuals with limited exposure to sunlight.
B. Metabolism of vitamin D
1. Formation of 1,25-diOH-D3: Vitamins D2 and D3 are not biologically active, but are converted in vivo to the active form of the D vitamin by two sequential hydroxylation reactions (Figure 28.23). The first hydroxylation occurs at the 25-position, and is catalyzed by a specific hydroxylase in the liver. The product of the reaction, 25-hydroxycholecalciferol (25-OH-D3, calcidol), is the predominant form of vitamin D in the plasma and the major storage form of the vitamin. 25-OH-D3 is further hydroxylated at the 1 position by 25-hydroxycholecalciferol 1- hydroxylase found primarily in the kidney, resulting in the formation of 1,25-diOH-D3 (calcitriol). [Note: This hydroxylase, as well as the liver 25-hydtoxylase, are cytochrome P450 (CYP) proteins].
2. Regulation of 25-hydroxycholecalciferol 1-hydroxylase: 1,25-diOH-D3 is the most potent vitamin D metabolite. Its formation is tightly regulated by the level of plasma phosphate and calcium ions (Figure 28.24). 25-Hydroxycholecalciferol 1-hydroxylase activity is increased directly by low plasma phosphate or indirectly by low plasma calcium, which triggers the release of parathyroid hormone (PTH). Hypocalcemia caused by insufficient dietary calcium thus results in elevated levels of plasma 1, 25-diOH-D3. 1-Hydroxylase activity is also decreased by excess 1,25-diOH-D3, the product of the reaction.
C. Function of vitamin D
The overall function of 1,25-diOH-D3 is to maintain adequate plasma levels of calcium. lt performs this function by: 1) increasing uptake of calcium by the intestine, 2) minimizing loss of calcium by the kidney, and 3) slimulating resorption of bone when necessary (see Figure 28.23).

1. Eflect of vitamin D on the intestine:
1,25-diOH-D3 stimulates intestinal absorption of calcium and phosphate. 1,25-diOH-D3 enters the intestinal cell and binds to a cytosolic receptor. The 1,25-dioH-D3-receptor complex then moves to the nucleus where it selectively interacts with the cellular DNA. As a result, calcium uptake is enhanced by an increased synthesis of a specific calcium-binding protein. Thus, the mechanism of action of 1,25-diOH-D3 is typical of steroid hormones.
2. Etfect of vitamin D on bone:
1,25-di OH-D3 stimulates the mobilization of calcium and phosphate from bone by a process that requires protein synthesis and the presence of PTH. The result is an increase in plasma calcium and phosphate. Thus, bone is an important reservoir of calcium that can be mobilized to maintain plasma levels.
D. Distribution and requirement of vitamin D
Vitamin D occurs naturally in fatty fish, liver, and egg yolk. Milk, unless it is artificially fortified, is not a good source of the vitamin. Adequate Intake (Al) for vitamin D is 200 lU to age 50, and 400-600 lU after age 50.
E. Clinical indications
1. Nutritional rickets: Vitamin D deficiency causes a net demineralization of bone, resulting in rickets in children and osteomalacia in adults (Figure 28.25). Rickets is characterized by the continued formation of the collagen matrix of bone, but incomplete mineralization, resulting in soft, pliable bones. In osteomalacia, demineralization of pre-existing bones increases their susceptibility to fracture. Insufficient exposure to daylight and/or deficiencies in vitamin D consumption occur predominantly in infants and the elderly. Vitamin D deficiency is more common in the northern latitudes, because less vitamin D synthesis occurs in the skin as a result of reduced exposure to ultraviolet light.
[Note: The recommended intake of 200 lU/day (which corresponds to 5 ?g of cholecalciferol) may be insufficient, because higher doses of 800 lU/day have been shown to reduce the incidence of osteoporotic fractures.] Sufficient levels of serum 25-hydroxycholecalciferol (>75 nmol/L) have been linked to fall prevention in older people as well as to increased muscle strength and bone mass.
2. Renal osteodystrophy: Chronic renal failure results in decreased ability to form the active form of vitamin D. Supplementation with calcitriol is an effective therapy. [Note: Vitamin D supplementation is accompanied by phosphate reduction therapy to prevent hyperphosphatemia (due to renal failure) and precipitation of calcium phosphate crystals.]
3. Hypoparathyroidism: Lack of parathyroid hormone causes hypocalcemia and hyperphosphatemia. These patients may be treated with calcitriol and calcium supplementation.
F. Toxicity ot vitamin D
Like all fat-soluble vitamins, vitamin D can be stored in the body and is only slowly metabolized. High doses (100,000 lU for weeks or months) can cause loss of appetite, nausea, thirst, and stupor. Enhanced calcium absorption and bone resorption results in hypercalcemia, which can lead to deposition of calcium in many organs, particularly the arteries and kidneys. The Upper Intake Level (UL) is 2000 lU/day.