Chemistry And Occurrence

Ultraviolet irradiation of several animal and plant sterols converts them to compounds possessing vitamin D activity. In animals, the principal precursor sterol is 7-dehydrocholesterol, which is synthesized in the skin; exposure to ultraviolet light in sunlight converts 7-dehydrocholesterol to cholecalciferol (vitamin D3; Figure 61-4). Ergosterol, which is present only in plants, is the precursor to vitamin D2 (ergocalciferol) and its derivatives. Derivatives of vitamin D2 and vitamin D3 are both biologically active—although some data suggest that the D3 hormones may be more potent in certain settings—and are widely available in a variety of commercial vitamin preparations.

vitamin D2 (25-OH-ergocalciferol)

calcitriol 1a,25-(OH)2 vitamin D3

1,25-(OH)2-ergocalciferol 1a,25-(OH)2 vitamin D2

figure 61-4 Photobiology and metabolic pathways of vitamin D production and metabolism. Numbering for select positions discussed in the text is shown.

vitamin D2 (25-OH-ergocalciferol)

calcitriol 1a,25-(OH)2 vitamin D3

1,25-(OH)2-ergocalciferol 1a,25-(OH)2 vitamin D2

figure 61-4 Photobiology and metabolic pathways of vitamin D production and metabolism. Numbering for select positions discussed in the text is shown.

human requirements and units The recommended daily dose of vitamin D is 400 IU, or 10 fig. Vitamin D intake in many individuals (e.g., premature infants, the elderly, and African Americans) may be inadequate; contributory factors include decreased intake of dairy products, decreased sun exposure and increased use of sunscreen, and increased prevalence and duration of exclusive breast-feeding.

absorption, fate, and excretion Both vitamins D2 and D3 are absorbed from the small intestine and transported as chylomicrons in the lymphatics. Bile salts are essential for adequate absorption. The primary route of vitamin D excretion also is the bile. Severe shortening or inflammation of the small bowel or hepatic or biliary dysfunction may cause overt vitamin D deficiency.

In the blood, vitamin D circulates bound to vitamin D-binding protein. Its plasma t1/2 is -24 hours, but it is stored in fat for prolonged periods.

metabolic activation Whether endogenously synthesized or acquired from diet, vitamin D requires modification to become biologically active. The primary active metabolite of vitamin D is calcitriol, which is formed by two successive hydroxylations (Figure 61-4).

The initial 25-hydroxylation occurs in the liver to form 25-OH-cholecalciferol or 25-OH-ergocalciferol (collectively termed 25-OHD). 25-OHD has a circulating t/2 of 19 days, and normal levels are 30-80 ng/mL. Because of its prolonged t122 and precursor role in the production of calcitriol, measurement of serum 25-OHD is the preferred test to evaluate sufficiency of body stores of vitamin D.

After production in the liver, 25-OHD enters the circulation, largely bound by vitamin D-binding protein. Final activation occurs predominantly in the kidney, where 1a-hydroxylase in the proximal tubule converts 25-OHD to calcitriol. This process is highly regulated (Figure 61-5). Calcitriol and 25-OHD also can be hydroxylated by another renal enzyme, 24-hydroxylase, to make compounds that have considerably lower biological activity and presumably are destined for excretion.

physiological functions and mechanism of action Calcitriol augments absorption and retention of Ca2+ and phosphate. The action of calcitriol is mediated by interaction with the VDR, a member of the nuclear receptor family. After binding to calcitriol, the VDR translocates to the nucleus and regulates the transcription of its target genes, likely as a heterodimer with the retinoid X receptor. Calcitriol also exerts nongenomic effects whose physiological relevance is unclear.

In the absence of calcitriol, calcium absorption throughout the small intestine is inefficient and involves passive diffusion via the paracellular pathway. Calcitriol in the proximal duodenum

25-ohd

oh ho''^-"'tih figure 61-5 Regulation of 1a-hydroxylase activity. Changes in the plasma levels of PTH, Ca2+, and phosphate modulate the hydroxylation of 25-OH vitamin D to the active form, 1,25-dihydroxyvitamin D. ABBREVIATIONS: 25-OHD, 25-hydroxycholecalciferol; 1,25-(OH)2D, calcitriol; PTH, parathyroid hormone.

stimulates the TRPV6 Ca2+ channels and also induces the synthesis of calbindin D9K calbindin D28k, and the serosal membrane Ca2+-ATPase. The net effect of these actions is to stimulate active calcium uptake.

Calcitriol's effects on bone are predominantly mediated by its actions to stimulate intestinal calcium uptake, although large doses can directly stimulate bone resorption. Similarly, there are direct effects of calcitriol to stimulate Ca2+ reabsorption in the distal tubule. The physiological impact of these effects is unknown.

The VDR is distributed widely throughout the body, and calcitriol actions extend well beyond calcium homeostasis. For example, calcitriol and synthetic analogs have been evaluated as antiproliferative agents for therapy of skin diseases (e.g., psoriasis) and cancer.

Calcitonin

Calcitonin is produced by the C cells of the thyroid gland; its actions generally oppose those of PTH. Calcitonin is a single-chain polypeptide hormone of 32 amino acids with an intrachain disulfide bridge. Salmon calcitonin, which differs from the human sequence at approximately half of the residues, is used therapeutically because it is more potent and is cleared more slowly from the circulation.

regulation of secretion Calcitonin secretion increases with hypercalcemia and decreases when plasma Ca2+is low; the hormone in circulation has a t1/2 of 10 minutes. Circulating concentrations are normally low (<15 pg/mL in males and 10 pg/mL in females) but can be markedly elevated with C cell hyperplasia or medullary thyroid cancer.

mechanism of action Calcitonin actions are mediated by the calcitonin receptor, a GPCR that couples through multiple G proteins to diverse signal transduction pathways. The hypocalcemic and hypophosphatemic effects of calcitonin result primarily from direct inhibition of osteoclast bone resorption.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook


Post a comment