Skin: site of the synthesis of vitamin D and a target tissue for the active form, 1,25-dihydroxyvitamin D3.
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Animals↗
Biomedical subjects
M F Holick
Publications and source records attributed to M F Holick.
The role of sunlight in the cutaneous production of vitamin D3.
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Cholecalciferol↗
Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.
Sunlight has long been recognized as a major provider of vitamin D for humans; radiation in the UVB (290-315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which, in turn, is converted by a thermal process to vitamin D3. Latitude and season affect both the quantity and quality of solar radiation reaching the earth's surface, especially in the UVB region of the spectrum, but little is known about how these influence the ability of sunlight to synthesize vitamin D3 in skin. A model has been developed to evaluate the effect of seasonal and latitudinal changes on the potential of sunlight to initiate cutaneous production of vitamin D3. Human skin or [3 alpha-3H]7-dehydrocholesterol exposed to sunlight on cloudless days in Boston (42.2 degrees N) from November through February produced no previtamin D3. In Edmonton (52 degrees N) this ineffective winter period extended from October through March. Further south (34 degrees N and 18 degrees N), sunlight effectively photoconverted 7-dehydrocholesterol to previtamin D3 in the middle of winter. These results quantify the dramatic influence of changes in solar UVB radiation on cutaneous vitamin D3 synthesis and indicate the latitudinal increase in the length of the "vitamin D winter" during which dietary supplementation of the vitamin may be advisable.
Alberta↗
Chronic sunscreen use decreases circulating concentrations of 25-hydroxyvitamin D. A preliminary study.
Sunscreens block the absorption of the sunlight spectrum responsible for the cutaneous synthesis of vitamin D (ultraviolet B). The present study was prompted by our observation of suppression of cutaneous vitamin D formation by a single application of sunscreening agents. We measured the index of vitamin D body store, serum 25-hydroxyvitamin D (25-OH-D) level, in 20 long-term users of p-aminobenzoic acid (PABA) and in 20 controls matched by age and exposure to sunlight. Serum 25-OH-D levels were significantly lower among long-term PABA users than among normal controls: 40.2 +/- 3.2 vs 91.3 +/- 6.2 nmol/L. Furthermore, vitamin D deficiency, ie, 25-OH-D levels below 20.0 nmol/L, was seen in two PABA users and in none of the controls. This preliminary study suggests that long-term use of PABA may be associated with low body stores of vitamin D in some persons.
Adult↗
Location of conjugated diene position in an aliphatic chain by mass spectrometry of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct.
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Alkadienes↗
Vitamin D and the kidney.
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Cholecalciferol↗
Sunscreens suppress cutaneous vitamin D3 synthesis.
Sunscreens block the cutaneous absorption of UV-B radiation and prevent sunburning, premature aging, and cancer of the skin. Inasmuch as UV-B radiation is also responsible for the photosynthesis of vitamin D3, we investigated the effect of sunscreens on the cutaneous formation of vitamin D3 in vivo and in vitro. Eight normal subjects, four of whom had been protected with the sunscreen para-aminobenzoic acid (sun protection factor 8), were exposed to one minimal erythema dose of UV radiation. The mean serum vitamin D3 concentration increased from 1.5 +/- 1.0 (+/- SEM) to 25.6 +/- 6.7 ng/mL in unprotected subjects, whereas it was 5.6 +/- 3.0 and 4.4 +/- 2.4 ng/mL at these times in the subjects who were protected with para-aminobenzoic acid. Para-aminobenzoic acid also prevented the photoisomerization of 7-dehydrocholesterol to previtamin D3 in human skin slices in vitro. These results indicate that the sunscreen interferred with the cutaneous production of vitamin D3.
4-Aminobenzoic Acid↗
Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis.
Vitamin D is a hormone, not a vitamin. The skin is responsible for producing vitamin D. During exposure to sunlight, ultraviolet radiation penetrates into the epidermis and photolyzes provitamin D3 to previtamin D3. Previtamin D3 can either isomerize to vitamin D3 or be photolyzed to lymisterol and tachysterol. Vitamin D is also sensitive to sunlight and is photolyzed to 5,6-transvitamin D3, suprasterol I, and suprasterol II. In Boston, solar irradiation only produces previtamin D3 in the skin between the months of March and October. Aging, sunscreens, and melanin all diminish the capacity of the skin to produce previtamin D3. Once formed, vitamin D3 enters the circulation and is sequentially metabolized to 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-[OH]2-D3). The epidermis possesses receptors for 1,25-(OH)2-D3. 1,25-(OH)2-D3 inhibits the proliferation of cultured keratinocytes and induces them to terminally differentiate. The topical or oral administration of 1,25-(OH)2-D3 has proved to be effective for the treatment of psoriasis. Therefore, the skin is the site for the synthesis of vitamin D and a target tissue for its active metabolite. The successful use of 1,25-(OH)2-D3 for the treatment of psoriasis heralds a new approach for the treatment of this enigmatic disorder.
Calcitriol↗
Photosynthesis of vitamin D in the skin: effect of environmental and life-style variables.
Exposure to sunlight continues to play a major role in providing adequate vitamin D nutrition for most of the population of the world, including those who live in countries that practice fortification of dairy, margarine, and cereal products with vitamin D. During exposure to sunlight, the high-energy UV photons (290-315 nm) penetrate the epidermis and photolyze 7-dehydrocholesterol (provitamin D3) to previtamin D3. Once formed, previtamin D3 undergoes a thermally induced isomerization to vitamin D3 that takes 2-3 days to reach completion. Melanin effectively competes with provitamin D3 for the UV radiation that enters the epidermis and limits its photolysis to previtamin D3. However, this is not the major factor that prevents excess production of vitamin D in the skin of people who are constantly exposed to sunlight. During the initial exposure to sunlight, provitamin D3 is efficiently converted to previtamin D3. However, because previtamin D3 is photolabile, continued exposure to sunlight causes the isomerization of previtamin D3, principally to lumisterol. Thus, no more than 10-20% of the initial provitamin D3 concentrations ultimately end up as previtamin D3. Aging, sunscreens, seasonal changes, time of day, and latitude also significantly affect the cutaneous production of this vitamin-hormone.
Aging↗
Photoaffinity labeling of the rat plasma vitamin D binding protein with [26,27-3H]-25-hydroxyvitamin D3 3 beta-[N-(4-azido-2-nitrophenyl)glycinate].
It is well recognized that the vitamin D binding protein (DBP) is important for the transport of vitamin D, 25-hydroxyvitamin D (25-OH-D), and its metabolites. In an attempt to better understand the molecular-binding properties of this ubiquitous protein, we designed and synthesized a photoaffinity analogue of 25-OH-D3 and its radiolabeled counterpart. This analogue, 25-hydroxyvitamin D3 3 beta-[N-(4-azido-2-nitrophenyl)glycinate] (25-OH-D3-ANG), was recognized by the rat DBP and was about 10 times less active than 25-OH-D3 in terms of binding. Incubation of [3H]25-OH-D3 or [3H]25-OH-D3-ANG with rat DBP revealed that both compounds were specifically bound to a protein with a sedimentation coefficient of 4.1 S. Each was displaced with a 500-fold excess of 25-OH-D3. When [3H]25-OH-D3-ANG was exposed to UV radiation in the presence of rat DBP followed by the addition of a 500-fold excess of 25-OH-D3, there was no displacement of tritium from the 4.1S peak. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiographic analysis of [3H]25-OH-D3-ANG exposed to UV radiation in the presence of rat DBP followed by the addition of a 500-fold excess of 25-OH-D3 revealed one major band with a molecular weight of 52 000. These data provide strong evidence that [3H]25-OH-D3-ANG was covalently linked to the rat DBP. This photoaffinity probe should provide a valuable tool for the analysis of the binding site on this transport protein.
Affinity Labels↗
Bone disease in prolonged parenteral nutrition: osteopenia without mineralization defect.
A metabolic bone disease characterized by a mineralization defect, low plasma 1,25(OH)2D, and hypercalciuria has been described in patients receiving prolonged total parenteral nutrition (TPN). Because the practice of TPN differs from center to center, we investigated 13 home TPN patients to determine whether they had similar or different bone abnormalities. They had received TPN for a mean period of 51 +/- 38 mo. Bone pain occurred in six patients and two had multiple vertebral and rib fractures (with trauma in one patient). Bone pain was mild to moderate and not incapacitating. Bone histomorphometry showed reduced bone volume, reduced osteoid with normal resorption and calcification rates. These abnormalities were associated with hypercalciuria, but the plasma levels of 1,25(OH)2D were normal. Abnormalities in bone metabolism in this group of patients suggest a fundamental decrease in bone matrix-formation rather than a mineralization defect as the underlying mechanism.
Adult↗
Indian and Pakistani immigrants have the same capacity as Caucasians to produce vitamin D in response to ultraviolet irradiation.
To investigate whether the high prevalence of osteomalacia and rickets among Indian and Pakistani immigrants to Great Britain is due to impaired capacity to produce vitamin D3 in their skin, the serum vitamin D concentrations of six Asians in response to 1.5 times their minimal erythemal dose (MED) of whole-body ultraviolet radiation (UVR) was studied. The mean serum vitamin D concentrations rose from a baseline of 2 +/- 2 ng/ml before exposure to UVR to a peak of 38 +/- 12 ng/ml at 24 h, gradually declining back to baseline by day 9. This response was not significantly different from that seen in Caucasian controls. The UVR needed to produce an MED in Asians, with their darker skin, was greater (49-133 mJ/cm2) than that required in Caucasians (31-48 mJ/cm2). Asians may need longer exposure to sunlight than Caucasians do to give a similar response, but the capacity to produce vitamin D is no different in Asian than in Caucasian skin.
Adolescent↗
Effect of 1 alpha,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions.
The effect of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2-D3] on the proliferation and morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown under defined, serum-free conditions was studied. 1 alpha,25-(OH)2-D3 caused a dose-dependent decrease in proliferation and an increase in the morphologic differentiation of human cultured keratinocytes. The number of attached basal cells decreased when exposed to 1 alpha,25-(OH)2-D3, whereas the number of attached squamous cells, terminally differentiated desquamated cells, and cornified cells increased concurrently. In addition, after incubation with 1 alpha,25-(OH)2-D3, there was a shift to cells of lighter density. In conjunction with its effect on the basal cells, 1 alpha,25-(OH)2-D3 resulted in an inhibition of DNA synthesis. The activity of transglutaminase, the enzyme responsible for cross-linking the proteins of the cornified envelope, was stimulated by 156% with 1 alpha,25-(OH)2-D3, but not with 1 beta,25-(OH)2-D3, a biologically inert isomer. Therefore it appears that 1 alpha,25-(OH)2-D3 is a potent inhibitor of keratinocyte proliferation as well as a stimulator of epidermal terminal differentiation.
Calcitriol↗
Effects of serum calcium and phosphorus on skeletal mineralization in vitamin D-deficient rats.
In the present study, we have evaluated the role of calcium and phosphorus concentrations in serum on the mineralization of bone in the absence of vitamin D. This was accomplished by feeding mother rats and subsequently their pups vitamin D-deficient diets varying in calcium, phosphorus, and lactose content. After 5-7 wk on these diets, serum concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-hydroxyvitamin D [1,25(OH)2D] were undetectable. Rats fed a vitamin D-deficient diet containing 0.44% calcium and 0.3% phosphorus showed a serum calcium of 4.9-5.9 mg/dl and a serum phosphorus of 7.3-8.2 mg/dl; rickets (wide epiphysial plates) had developed as well as osteomalacia (wide osteoid seams). Rats maintained on a vitamin D-deficient diet containing 3% calcium and 0.65% phosphorus had normal serum calcium, low serum phosphorus, and severe rickets, but osteomalacia was not seen. Rats fed a diet containing 20% lactose, 4% calcium, and 1% phosphorus showed normal serum calcium, somewhat low serum phosphorus, normal serum PTH, normal width of the epiphysial plate, normal volume density of trabecular bone, and normal volume density of osteoid seams. These data confirm the findings of others, using a different experimental model, that serum calcium and phosphorus concentrations are the determining factors in mineralization defects and not the absence of 25(OH)D or 1,25(OH)2D. In these rats thyroparathyroidectomy is well tolerated, which makes for an ideal model for the study of the effects of calcium-regulating hormones on bone histology, cytology, and biochemistry.
Animals↗
Evaluation of a photolabile derivative of 1,25-dihydroxyvitamin D3 as a photoaffinity probe for 1,25-dihydroxyvitamin-D3 receptor in chick intestinal cytosol.
We evaluated the viability of 1 alpha, 25-dihydroxyvitamin D3-3 beta-[N-(4-azido-2-nitrophenyl)glycinate] (1,25-(OH)2-D3-ANG), an analog of 1 alpha, 25-dihydroxyvitamin D3 (1,25-(OH)2-D3) as a photoaffinity probe for 1,25-(OH)2-D3 receptor in chick intestinal cytosol. A competitive-binding assay revealed that chick intestinal cytosolic 1,25-(OH)2- D3 receptor bound to 1,25-(OH)2-D3-ANG approximately 20-times less effectively than it did to 1,25-(OH)2-D3. Irradiation of 1,25-(OH)2-D3- ANG in the presence of chick intestinal cytosolic preparation significantly diminished subsequent binding to 3H-1,25-(OH)2-D3, suggesting that the photoaffinity analog was covalently attached to the receptor. Therefore the nitroarylazide derivative of 1,25-(OH)2-D3 may be a valuable photoaffinity probe for the characterization of the 1,25-(OH)2-D3 receptor.
Affinity Labels↗
Isolation and identification of 24-dehydroprovitamin D3 and its photolysis to 24-dehydroprevitamin D3 in mammalian skin.
Until now it had been assumed that mammalian skin contains only one provitamin D, 7-dehydrocholesterol, that is eventually converted to vitamin D3 after the skin is exposed to sunlight. Examination by reverse phase high performance liquid chromatography of lipid extracts from young rat skin, however, led to the observation that 7-dehydrocholesterol is not the only provitamin D in rat skin. Another provitamin D, accounting for 22 +/- 3% of the total provitamin content of the skin, was resolved from 7-dehydrocholesterol, and, on the basis of ultraviolet spectrophotometry, mass spectrometry, and nuclear magnetic resonance spectrometry, was identified as 24-dehydroprovitamin D3 (cholesta-5,7,24-trien-3 beta-ol). This new cutaneous provitamin D is not unique to the rat because it was also detected in the skin of reptiles, amphibians, birds, aquatic mammals, and humans. To be certain that the cutaneous 24-dehydroprovitamin D3 was as susceptible as 7-dehydrocholesterol to ultraviolet photolysis, rat skin was exposed to ultraviolet radiation. A reverse phase high performance liquid chromatographic analysis of a lipid extract of rat skin previously exposed to ultraviolet radiation demonstrated the presence of both previtamin D3 and 24-dehydroprevitamin D3. Therefore, these observations demonstrate for the first time that mammalian skin has the capacity to produce not one but at least two different vitamin Ds.
Animals↗
Cultured psoriatic fibroblasts from involved and uninvolved sites have a partial but not absolute resistance to the proliferation-inhibition activity of 1,25-dihydroxyvitamin D3.
We examined the responsiveness of cultured dermal fibroblasts from biopsies of uninvolved and involved areas of skin from six patients with psoriasis to the cell-proliferation-inhibition activity of 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3). Cultured fibroblasts from age-matched controls responded to 1,25-(OH)2-D3 (at 0.01, 1, 10, and 100 microM) in a dose-dependent fashion, whereas cultured psoriatic fibroblasts from involved or uninvolved skin showed no inhibition of proliferation when exposed to 0.01 or 1 microM of 1,25-(OH)2-D3. However, 1,25-(OH)2-D3 did inhibit proliferation of cultured psoriatic fibroblasts when the concentrations were increased to 10 and 100 microM. An analysis of the 1,25-(OH)2-D3 receptors in cultured psoriatic fibroblasts from uninvolved skin revealed that the Kd, nmax, and sedimentation coefficient were identical to the receptors found in the fibroblasts from age-matched controls. Therefore, cultured psoriatic fibroblasts from involved and uninvolved skin have a partial resistance to 1,25-(OH)2-D3, suggesting that there may be a biochemical defect that is inherent in the dermal fibroblasts of psoriatic patients. Recognition of this defect may provide a new approach for the evaluation of the cause and treatment of this disfiguring skin disorder.
Calcitriol↗
Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes.
We developed a test procedure for the clinical evaluation of the absorption of vitamin D. Serum vitamin D concentrations were evaluated in seven patients with intestinal fat malabsorption syndromes and in seven healthy, normal subjects, after being given a single oral dose of 50,000 IU (1.25 mg) vitamin D2. In the normal subjects, serum vitamin D concentrations rose from a baseline of less than 5 ng/ml to a peak of over 50 ng/ml by 12 h, gradually falling to baseline levels by 3 days. In five of the seven patients with intestinal fat malabsorption, oral administration of 50,000 IU vitamin D2 did not raise serum vitamin D concentrations above 10 ng/ml. Two patients with severe inflammatory bowel disease had a normal absorption pattern, however. These findings suggest that an oral vitamin D absorption test may be of value for determination of patients at risk for development of vitamin D deficiency. They also raise questions about the efficacy of oral vitamin D preparations in patients with intestinal fat malabsorption.
Adult↗