Cholecalciferol is formed nonenzymically in the skin by UV irradiation of 7-dehydrocholesterol, as shown in Figure 3.2. 7-Dehydrocholesterol is an
HO v calciol (cholecalciferol) Figure 3.2. Synthesis of calciol from 7-dehydrocholesterol in the skin.
intermediate in the synthesis of cholesterol that accumulates in the skin, but not other tissues. It is synthesized in the sebaceous glands, secreted onto the surface of the skin, and then absorbed into the epidermis. It is found throughout the epidermis and dermis, with the highest concentration per unit surface area in the stratum basale and stratum spinosum, which therefore have the highest capacity for cholecalciferol synthesis. One of the possible causes of vitamin D deficiency in the elderly, in addition to low exposure to sunlight, is an age-dependent decrease in the concentration of 7-dehydrocholesterol in the epidermis - hence a reduction in the capacity for endogenous cholecalciferol synthesis.
On exposure to UV light, 7-dehydrocholesterol undergoes photolysis, with cleavage of the B-ring and inversion of the A-ring, to yield precalciferol (pre-vitamin D or tacalciol). The peak wavelength for this photolysis is 296.5 nm; for practical purposes, the useful range of solar radiation is the UV-B range, between 290 nm (the lowest wavelength transmitted by ozone) and 320 nm. At 310 nm, however, the yield of precalciferol is only 1% of that at 296.5 nm. Precalciferol undergoes thermal isomerization to cholecalciferol. This is a slow process; at 37° C, there is 50% isomerization within 48 hours, and, after 4 days, equilibrium is reached in vitro with about 83% cholecalciferol. In vivo, isomerization is somewhat more rapid because the equilibrium is shifted by the removal of cholecalciferol bound to plasma vitamin D binding protein.
As discussed in Section 3.6.1, excess oral vitamin D results inhypercalcemia; toxicity is associated with plasma concentrations of calcidiol above 400 nmol perL. However, evenexcessiveexposuretosunlightdoesnotresultinvitaminD intoxication, and the plasma concentration of calcidiol does not rise above 100 to 200 nmol per L. During prolonged UV irradiation of the skin, the concentration of precalciferol does not rise above 10% to 15% of the initial concentration of 7-dehydrocholesterol. This is because photolysis of 7-dehydrocholesterol is reversible; light-catalyzed closure of the B-ring can result in formation of either 7-dehydrocholesterol or lumisterol, in which the 19-methyl group has the opposite configuration. In addition, precalciferol undergoes photoisomer-ization to tachysterol, which is biologically inactive; and cholecalciferol is also sensitive to photodegradation, yielding 5,6-frans-cholecalciferol and biologically inactive suprasterols. There is no evidence that the cutaneous synthesis of cholecalciferol is regulated by vitamin D status, and the administration of calcitriol has no effect on the increase in serum calcidiol after exposure to UV irradiation. Because of both the slow isomerization of precalciferol to chole-calciferol and photoisomerization to inactive compounds, skin pigmentation seems not to affect the total amount of cholecalciferol formed to any significant extent.
Sunlight is not strictly essential for cutaneous synthesis of cholecalciferol, because UV-B penetrates clouds reasonably well; complete cloud cover reduces the available intensity by about 50%. It also penetrates light clothing. However, low-intensity irradiation (below 20 mJ per cm2 in vitro) does not result in significant photolysis of 7-dehydrocholesterol to previtamin D. Acute whole-body exposure to UV-B irradiation below 18 mJ per cm2 does not result in any detectable increase in plasma cholecalciferol or calcidiol. In temperate regions (beyond about 40°N or S), the intensity of UV-B is below this threshold in winter, so there is unlikely to be any significant cutaneous synthesis of the vitamin in winter, and plasma concentrations of calcidiol show a marked seasonal variation in temperate regions (Holick, 1995; see Table 3.2).
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