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], or calcitriol), binds to intracellular receptor proteins.

The most prominent actions of calcitriol are to regulate the serum levels of calcium and phosphorus.

Distribution

1-Endogenous vitamin precursor:

   7-Dehydrocholesterol, an intermediate in cholesterol synthesis, is converted to cholecalciferol in the dermis and epidermis of humans exposed to sunlight and transported to liver bound to vitamin D–binding protein.

2.Diet:

  Ergocalciferol (vitamin D2), found in plants,

and cholecalciferol (vitamin D3), found in animal tissues, are sources of preformed vitamin D activity.

Vitamin D2 and vitamin D3 differ chemically only in the presence of an additional double-bond and methyl group in the plant sterol.

Dietary vitamin D is packaged into chylomicrons. [Note: Preformed vitamin D is a dietary requirement only in individuals with
limited exposure to sunlight.

 Vitamins D2 and D3 are first converted to calcidiol 25-hydroxycholecalciferol ([25-OH-D3] and then to calcitriol  1,25-diOH-D3 = 1,25-dihydroxycholecalciferol. (active vitamin D).

Note: 7-Dehydrocholesterol (provitamin D3) is decreased in the skin of older adults.

Metabolism.

1. 1,25-Dihydroxycholecalciferol formation:

Vitamins D2 and D3 are not biologically active but are converted in vivo to calcitriol, the active form of the D vitamin, by two sequential hydroxylation reactions.

The first hydroxylation occurs at the 25 position and is catalyzed by a specific 25-hydroxylase in the liver. The product of the reaction, 25-
hydroxycholecalciferol ([25-OH-D3], calcidiol), is the predominant form of vitamin D in the serum and the major storage form.

The second hydroxylation 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: Both hydroxylases are cytochrome P450 proteins.]

Hydroxylation regulation:

Calcitriol is the most potent vitamin D metabolite. Its formation is tightly regulated by the level of serum phosphate (PO43-) and calcium ions (Ca2+).

25- Hydroxycholecalciferol 1-hydroxylase activity is increased directly by low serum PO43- or indirectly by low serum Ca2+, which triggers the secretion of parathyroid hormone (PTH) from the chief cells of the
parathyroid gland.

PTH upregulates the 1-hydroxylase. Thus, hypocalcemia caused by insufficient dietary Ca2+ results in elevated levels of serum 1,25-diOH-D3.

[Note: 1,25-diOH-D3 inhibits expression of PTH, forming a negative feedback loop. It also inhibits activity of the 1-hydroxylase.]

[Note: Calcitriol also increases intestinal absorption and renal reabsorption of phosphate. In contrast, PTH decreases renal reabsorption of phosphate.]

Function

The overall function of calcitriol is to maintain adequate serum levels of Ca2+. It performs this function by

1) increasing uptake of Ca2+ by the intestine,

2) minimizing loss of Ca2+ by the kidney by increasing reabsorption,

3) stimulating resorption (demineralization) of bone when blood Ca2+ is low

Effect on the intestine:

Calcitriol stimulates intestinal absorption of Ca2+ by first entering the intestinal cell and binding to a cytosolic receptor.
The 1,25-diOH-D3–receptor complex then moves to the nucleus where it selectively interacts with response elements on the DNA. As a result, Ca2+ uptake is enhanced by increased expression of the calcium-binding protein calbindin.

Effect on bone:

Bone is composed of collagen and crystals of Ca5(PO4)3OH (hydroxylapatite).

When blood Ca2+ is low, 1,25-diOH-D3 stimulates bone resorption by a process that is enhanced by PTH. The result is an increase in serum Ca2+. Therefore, bone is an important reservoir of Ca2+ that can be mobilized to maintain serum levels.

[Note: PTH and calcitriol also work together to prevent renal loss of Ca2+.]

Distribution and requirement

Vitamin D occurs naturally in fatty fish, liver, and egg yolk. Milk, unless it is artificially fortified, is not a good source.

The RDA (Recommended Dietary Allowances) for individuals

 ages 1–70 years is 15 µg/day and 20 µg/day if over age 70 years. [Note: 1 µg vitamin D = 40 international units (IU).]

breast milk is a poor source of vitamin D, supplementation is recommended for breastfed babies.

Clinical indications for vitamin D

Nutritional rickets:

Vitamin D deficiency causes a net demineralization of bone, resulting in rickets in children and osteomalacia in adults.

Rickets is characterized by the continued formation of the collagen matrix of bone, but incomplete mineralization results in soft,
pliable bones.

In osteomalacia, demineralization of preexisting bones increases their susceptibility to fracture.

Renal osteodystrophy:

Chronic kidney disease causes decreased ability to
form active vitamin D as well as increased retention of PO43-, resulting in hyperphosphatemia and hypocalcemia.

The low blood Ca2+ causes a rise in PTH and associated bone demineralization with release of Ca2+ and PO43-.

Supplementation with vitamin D is an effective therapy. However, supplementation must be accompanied by PO43- reduction therapy to prevent further bone loss and precipitation of calcium phosphate crystals.

Hypoparathyroidism

Hypoparathyroidism: Lack of PTH causes hypocalcemia and
hyperphosphatemia.

[Note: PTH increases phosphate excretion.]

Patients may be treated with vitamin D and calcium supplementation

See you later, in another topic in Biochemistry!!!!!!!