The biochemistry of Vitamin D is complex and fascinating. I remember studying hard when I was taking Biochemistry classes to get everything straight!

Vitamin D is a steroid hormone that plays an important role in regulating body levels of calcium and phosphorus, and in the mineralization of bone. Receptors for vitamin D are present in a wide variety of cells, and this hormone has biologic effects which extend far beyond control of mineral metabolism.

The generic term "Vitamin D" actually refers to a group of steroid molecules. Vitamin D3, also known as cholecalciferol is generated in the skin of animals when light energy is absorbed by a precursor molecule 7-dehydrocholesterol. Vitamin D is thus not a true vitamin, because individuals with adequate exposure to sunlight do not require dietary supplementation. There are dietary sources of vitamin D, including egg yolk, fish oil and a number of plants. The plant form of vitamin D is called vitamin D2 or ergosterol. The typical diet does not contain enough vitamin D, and exposure to sunlight or consumption of foodstuffs purposefully supplemented with vitamin D are necessary to prevent deficiencies.

Vitamin D, as either D3 or D2, does not have significant biological activity. Rather, it must be metabolized within the body to the hormonally-active form. This transformation occurs in two steps. In the liver, cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by the enzyme 25-hydroxylase.

Within the kidney, 25-vitamin D serves as a substrate for 1-alpha-hydroxylase, yielding 1,25-dihydroxycholecalciferol. This is the biologically active form of vitamin D. Each of the forms of vitamin D is hydrophobic (does not dissolve in water) and is transported in blood bound to carrier proteins. The major carrier is called, appropriately, vitamin D-binding protein. The half-life of 25-hydroxycholecalciferol is several weeks, while that of 1,25-dihydroxycholecalciferol is only a few hours.

Hepatic synthesis of 25-hydroxycholecalciferol is loosely regulated, and blood levels of this molecule largely reflect the amount of amount of vitamin D produced in the skin or ingested. In contrast, the activity of 1-alpha-hydroxylase in the kidney is tightly regulated and serves as the major control point in production of the active hormone. The major inducer of 1-alpha-hydroxylase is parathyroid hormone; it is also induced by low blood levels of phosphate.

The active form of vitamin D binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like the receptors for other steroid hormones (like estrogen) and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor. The heterodimer that is formed is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription. The vitamin D receptor binds several forms of cholecalciferol. Its affinity for 1,25-dihydroxycholecalciferol is roughly 1000 times that for 25-hydroxycholecalciferol, which explains their relative biological potencies.

Vitamin D is well known for its role in mineral metabolism and bone growth. Its most dramatic effect is to facilitate intestinal absorption of calcium, although it also stimulates absorption of phosphate and magnesium ions. In the absence of vitamin D, dietary calcium is not absorbed efficiently. Vitamin D stimulates the expression of a number of proteins involved in transporting calcium from the lumen of the intestine, across the epithelial cells and into blood. The best-studied of these calcium transporters is calbindin, an intracellular protein that ferries calcium across the intestinal epithelial cell.

Numerous effects of vitamin D on bone have been demonstrated. As a transcriptional regulator of bone matrix proteins, it induces the expression of osteocalcin and suppresses synthesis of type I collagen. In cell cultures, vitamin D stimulates differentiation of osteoclasts (cells that break down bone). However, studies of humans and animals with vitamin D deficiency or mutations in the vitamin D receptor suggest that these effects are perhaps not of major physiologic importance, and that the crutial effect of vitamin D on bone is to provide the proper balance of calcium and phosphorus to support mineralization.

Vitamin D receptors are present in most if not all cells in the body. Additionally, experiments using cultured cells have demonstrated that vitamin D has potent effects on the growth and differentiation of many types of cells. These findings suggest that vitamin D has physiologic effects much broader that a role in mineral homeostasis and bone function.

The classical manifestations of vitamin D deficiency is rickets, which is seen in children and results in bony deformaties including bowed long bones. Deficiency in adults leads to the disease osteomalacia. Both rickets and osteomalacia reflect impaired mineralization of newly synthesized bone matrix, and usually result from a combination of inadequate exposure to sunlight and decreased dietary intake of vitamin D.

Vitamin D deficiency or insufficiency occurs in several other situations. There are a number of mutations in the vitamin D receptor, which leads to problems with the receptor's function and leads to hereditary vitamin D resistance. Also, severe liver or kidney disease can interfere with generation of the biologically-active form of vitamin D. Elderly people that stay inside and have poor diets often have at least subclinical deficiency.

Excessive exposure to sunlight does not lead to overproduction of vitamin D. Vitamin D toxicity is inevitably the result of overdosing on vitamin D supplements. Ingestion of milligram quantities of vitamin D over periods of weeks of months can be severely toxic to humans and animals. In fact, baits laced with vitamin D are used very effectively as rodenticides. Ew!

~Faustina