The major function of the fat-soluble vitamin D is the maintenance of adequate plasma levels of calcium and phosphorus to support metabolic functions, bone mineralization, and neuromuscular transmission. In this capacity, the vitamin is required for the prevention of bone diseases known as rickets (in children whose epiphyses have not already closed), osteomalacia (in adults), and hypocalcemic tetany. With respect to tetany, vitamin D maintains the correct concentration of ionized calcium in the extracellular fluid compartment. When deficiency develops, the drop in ionized calcium in the extracellular fluid results in continuous excitation of muscle (tetany). It should be noted, however, that any reduction in the level of serum calcium is rapidly corrected by excess secretion of parathyroid hormone. Hence tetany is quite uncommon. Our attention here is focused on the function of vitamin D in the regulation of serum calcium levels.
Metabolism. The major source of vitamin D for humans is its endogenous synthesis in the skin by photochemical conversion of a precursor, 7-dehydrocholesterol, powered by the energy of solar or artificial UV light. Irradiation of this compound forms cholecalciferol, known as vitamin D3; in the following discussion, for the sake of simplicity, the term vitamin D is used to refer to this compound. Under usual conditions of sun exposure, approximately 90% of the vitamin D needed is endogenously derived from 7-dehydrocholesterol present in the skin. However, blacks may have a lower level of vitamin D production in the skin because of melanin pigmentation (perhaps a small price to pay for protection against UV-induced cancers). The small remainder comes from dietary sources, such as deep-sea fish, plants, and grains. In plant sources, vitamin D is present in a precursor form, ergosterol, which is converted to vitamin D in the body.
The metabolism of vitamin D can be outlined as follows (
Fig. 8.20): 1.
Absorption of vitamin D along with other fats in the gut or synthesis from precursors in the skin 2.
Binding to plasma α1-globulin (vitamin D–binding protein) and transport to liver 3.
Conversion to 25-hydroxyvitamin D (25-OH-D) by 25-hydroxylase in the liver 4.
Conversion of 25-OH-D to 1,25-dihydroxyvitamin D [1,25-(OH)2-D] (biologically the most active form of vitamin D) by α1-hydroxylase in the kidney
Renal production of 1,25-(OH)2-D is regulated by three mechanisms:
Hypocalcemia stimulates secretion of parathyroid hormone (PTH), which in turn augments the conversion of 25-OH-D to 1,25-(OH)2-D by activating α1-hydroxylase.
Hypophosphatemia directly activates α1-hydroxylase, thereby increasing the formation of 1,25(OH)2-D.
In a feedback loop, increased levels of 1,25-(OH)2-D downregulate the synthesis of this metabolite by inhibiting the action of α1-hydroxylase (decreases in 1,25(OH)2-D have the opposite effect).
Functions. Like retinoids and steroid hormones, 1,25(OH)2-D acts by binding to a high-affinity nuclear receptor that in turn binds to regulatory DNA sequences, thereby inducing transcription of specific target genes. The receptors for 1,25-(OH)2-D are present in most nucleated cells of the body, and they transduce signals that result in various biologic activities, beyond those involved in calcium and phosphorus homeostasis. Nevertheless, the best-understood functions of vitamin D relate to the maintenance of normal plasma levels of calcium and phosphorus, through action on the intestines, bones, and kidneys (