The production of 1,25-dihydroxyvitamin D3 begins in the skin, where vitamin D3 is produced from its precursor molecule (7-dehydrocholesterol) under the influence of sunlight. In equatorial regions of the globe, exposure to sunlight can allow sufficient cutaneous production of vitamin D3. In more northerly or southerly latitudes, however, exposure to the winter sun may not allow sufficient production of vitamin D3. When the skin does not make sufficient amounts of vitamin D3, this compound must be ingested in the diet—that is why it is called a vitamin. Whether this compound is secreted into the blood from the skin or enters the blood after being absorbed from the intestine, vitamin D3 functions as a prehormone; in order to be biologically active, it must be chemically changed (chapter 11).
An enzyme in the liver adds a hydroxyl group (OH) to carbon number 25, which converts vitamin D3 into 25-hydroxy vitamin D3. In order to be active, however, another hydroxyl group must be added to carbon number 1. Hydroxylation of the first carbon is accomplished by an enzyme in the kidneys, which converts the molecule to 1,25-dihydroxyvitamin D3 (fig. 19.20).
■ Figure 19.19 Scanning electron micrographs of bone. These biopsy specimens were taken from the iliac crest. Compare bone thickness in (a) a normal specimen and (b) a specimen from a person with osteoporosis.
From L. G. Raisz, S. W. Dempster, et al., "Mechanisms of Disease" in New England Journal of Medicine, Vol. 218 (I3):8I8. Copyright © 1988 Massachusetts Medical Society. All rights reserved.
The activity of this enzyme in the kidneys is stimulated by parathyroid hormone (fig. 19.21). Increased secretion of PTH, stimulated by low blood Ca2+, is thus accompanied by the increased production of 1,25-dihydroxyvitamin D3.
The hormone 1,25-dihydroxyvitamin D3 helps to raise the plasma concentrations of calcium and phosphate by stimulating (1) the intestinal absorption of calcium and phosphate, (2) the resorption of bones, and (3) the renal reabsorption of calcium and phosphate so that less is excreted in the urine. Notice that 1,25-dihydroxyvitamin D3, but not parathyroid hormone, directly stimulates intestinal absorption of calcium and phosphate and promotes the reabsorption of phosphate in the kidneys. The
626 Chapter Nineteen
■ Figure 19.21 The negative feedback control of parathyroid hormone secretion. A decrease in plasma Ca2+ directly stimulates the secretion of parathyroid hormone (PTH). The production of 1,25-dihydroxyvitamin D3 also rises when Ca2+ is low because PTH stimulates the final hydroxylation step in the formation of this compound in the kidneys.
Decreased plasma Ca2+
Increased 1a-hydroxylase activity
Increased plasma Ca2+
25-Hydroxyvitamin D3 (from liver)
effect of simultaneously raising the blood concentrations of Ca2+ and PO43- results in the increased tendency of these two ions to precipitate as hydroxyapatite crystals in bone.
Since 1,25-dihydroxyvitamin D3 directly stimulates bone resorption, it seems paradoxical that this hormone is needed for proper bone deposition and, in fact, that inadequate amounts of 1,25-dihydroxyvitamin D3 result in the bone demineralization of osteomalacia and rickets. This apparent paradox may be explained by the fact that the primary function of 1,25-dihydroxyvitamin D3 is stimulation of intestinal Ca2+ and PO43- absorption. When calcium intake is adequate, the major result of 1,25-dihydroxyvitamin D3 action is the availability of Ca2+ and PO43- in sufficient amounts to promote bone deposition. Only when calcium intake is inadequate does the direct effect of 1,25-dihydroxyvitamin D3 on bone resorption become significant, acting to ensure proper blood Ca2+ levels.
In addition to osteoporosis, a number of other bone disorders are associated with abnormal calcium and phosphate balance. In osteomalacia (in adults) and rickets (in children), inadequate intake of vitamin D results in inadequate calcification of the organic matrix in bones. Excessive secretion of parathyroid hormone results in osteitis fibrosa cystica, in which excessive osteoclast activity causes resorption of both the mineral and organic components of bone, which are then replaced by fibrous tissue.
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