VITAMIN-D

Vitamin D is a group of fat-soluble secosteroids responsible for enhancing intestinal absorption of calcium, phosphate and in mineralization of bone. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol) in plants.
Vitamin D is commonly called a vitamin, it is not actually an essential dietary vitamin in the strict sense because vitamins are defined as organic dietary constituents necessary for life and development, but that do act as dietary energy source. In that aspect, it has been argued that the term vitamin D is a misnomer because normally the active hormonal form of vitamin D is produced within the body from the dietary substrates or endogenous substances. So, it is accepted that vitamin D is not a vitamin but rather a precursor of one or more steroid like hormone produced by specific tissues within the body.
The body can also synthesize vitamin D (specifically cholecalciferol) in the skin, from cholesterol, when sun exposure is adequate. The receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism.

TYPES:

Several forms (vitamers) of vitamin D exists. The two major forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol); vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol. 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. The various forms of vitamin D are secosteroids; i.e.,  steroids in which one of the bonds in the steroid rings is broken. The structural difference between D2 and D3 is their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.

BIOSYNTHESIS:

Vitamin D is produced in the two layers of skin, the stratum Basale and stratum spinosum. 

Vitamin D3 (cholecalciferol) is produced through the action of ultraviolet irradiation(UV) on its precursor 7-dehydrocholesterol. Our skin makes vitamin D3 and supplies about 90 percent of our vitamin D. This molecule occurs naturally in the skin of animals and in milk.

Vitamin D2 is a derivative of ergosterol, a membrane sterol named for the ergot fungus, which is produced by some kinds of phytoplankton, invertebrates, yeasts and higher fungi such as mushrooms. The vitamin ergocalciferol (D2) is produced in all of these organisms from ergosterol, in response to UV irradiation. Like all forms of vitamin D, it cannot be produced without UV irradiation. D2 is not produced by green plants or vertebrates, because they lack the precursor ergosterol.

Vitamin D3 (cholecalciferol) is produced photochemically in the skin from 7-dehydrocholesterol. The precursor of vitamin D3, 7-dehydrocholesterol is produced in relatively large quantities, 10,000 to 20,000 IU of vitamin D are produced in 30 minutes of whole-body exposure, in the skin of most vertebrate animals , including humans.

7-dehydrocholesterol is first converted to provitamin D3, which subsequently equilibrates in the skin to form cholecalciferol through a temperature dependent thermal isomerization. Cholecalciferol is transported by a binding protein (transcalciferin) present in normal circulation. Under continues exposure to the sun provitamin D3 also photo isomerize to lumisterol and tachysterol, which are biologically inert. These isomers are in quasi-stationary state serve as reserve substrate for photo conversion back to provitamin D3 which later converted to vitamin D3. These isomers remain in the skin and cannot be translocated into the circulation. Cholecalciferol is converted to 25-hydroxyvitamin D3 in the LIVER. Liver is the major site of 25-hydroxylation in mammals. This steroid is the major circulating metabolite of cholecalciferol, it must undergo one other chemical modification before it can function as hormone. 25-OH-D3 is circulated to kidney where it is converted by a mitochondrial 1-alpha-hydroxylase to 1-alpha , 25 (OH)2 D3, the hormonal form of cholecalciferol. The 1,25 (OH)2 D3 products was originally detected in chick intestinal chromatin, one of its now recognized site of action. 1,25 (OH)2 D3 functions as a hormone in classical sense because it must be carried by the blood from its site of synthesis to its target cells. Cholecalciferol and its hydroxylated metabolites, 25-OH-D3 and other hydroxylated metabolites are bound to a plasma protein, originally referred to in the human as trans calcefrin or calciferol binding protein.

Another enzyme present in the kidney mitochondria and possibly other extrarenal sites, 25-hydroxycholecalciferol, produces 24,25 (OH)2 D3, which is inactive biologically in mammals. A trihydroxylated derivative of  vitamin D3 , 1,24,25- trihydroxy cholecalciferol, as also been isolated from the plasma, but it too is biologically inactive. 25,26-hydroxy cholecalciferol has been isolated from the blood of humans and some animals receiving pharmacologist doses of cholecalciferol.

REGULATION OF VITAMIN D METABOLISM

A kidney 1-alpha-hydroxylase is the key enzyme in 1,25 (OH)2 D3 biosynthesis, it might be expected to be tightly regulated by endocrine or other factors under condition of hypocalcemia. There is a strict inverse relationship between the serum Ca2+ level and the ability to of animals to produce 1,25 (OH)2 D3. Conversely, whenever 1,25 (OH)2 D3 synthesis is suppressed, 24,25 (OH)2 D3 synthesis is stimulated. Removal of the parathyroid gland eliminates the hypocalcemic stimulation of 1,25 (OH)2 D3 production and 24,25 (OH)2 D3 is produced. PTH restores the ability of hypocalcemic animals to make 1,25 (OH)2 D3 and suppresses the production of 24,25 (OH)2 D3. PTH alters 25-OH-D3 metabolism through the cAMP-mediated mechanism. The metabolic tendency of the kidney to produce primarily 1,25 (OH)2 D3 or 24,25 (OH)2 D3 is subject to dynamic modulation by the opposing effects of 1,25 (OH)2 D3 and PTH either directly or indirectly.

 The feedback mechanism regulating 1,25 (OH)2 D3 production can be summarized as follows:

• Hypocalcemia is stimulatory to PTH secretion from the parathyroid.
• PTH stimulates renal cortical 1-aplha-OHase activity and 1,25 (OH)2 D3 biosynthesis.

1,25 (OH)2 D3 stimulates Ca2+ absorption from the gut, increase release of Ca2+ from the bones and stimulates Ca2+ reabsorption from the kidney.

Increasing levels of Ca2+ then feedback to inhibit further synthesis of PTH.

PTH stimulates renal excretion of phosphate. Low plasma levels of PO43- are directly stimulatory to renal 1-alpha-OHase activity and 1,25 (OH)2 D3 production, whereas elevated levels of PO43- are inhibitory to production of the hormone. The plasma concentration of phosphate may therefore be an important local regulator of renal 1,25 (OH)2 D3 biosynthesis. Although the synthesis of 1,25 (OH)2 D3 can be stimulated directly by low plasma PO43- concentration, this hypophosphatemia does not stimulate PTH secretion.