1-alpha-24-dihydroxyvitamin-d3 and Hypercalcemia

Topics: Calcitriol; Dermatologic Agents; Dihydroxycholecalciferols; Etretinate; Humans; Hypercalcemia; Hyperkeratosis, Epidermolytic; Keratin-10; Male; Mutation, Missense; Young Adult

Topics: Adult; Dermatologic Agents; Dihydroxycholecalciferols; Humans; Hypercalcemia; Male; Pancreatitis, Acute Necrotizing; Psoriasis

Tacalcitol is a synthetic vitamin D3 analogue developed for topical treatment of inflammatory skin diseases such as psoriasis. Hypercalcemia has not been previously reported during treatment with topical tacalcitol. We experienced a male patient with psoriasis and hypertension whose conditions were treated with tacalcitol ointment and thiazide, respectively, resulting in hypercalciuria and hypercalcemia. After initiation of topical vitamin D3 ointment (20 micro g/g of tacalcitol) 10 g/day for the skin lesions, both the serum level of calcium and urinary excretion of calcium increased gradually. On day 28 of the treatment, his serum calcium levels had reached 3.55 mmol/l, and his urinary calcium excretion had also increased from 0.008 g/day to 0.475 g/day. The tacalcitol treatment was terminated, seven days later, the serum calcium level had returned to the reference range without any specific treatment. The present case is the first report of hypercalcemia induced by vitamin D3 ointment and thiazide simultaneously.

Topics: Administration, Cutaneous; Aged; Benzothiadiazines; Calcium; Dermatologic Agents; Diagnosis, Differential; Dihydroxycholecalciferols; Diuretics; Humans; Hypercalcemia; Hypertension; Iatrogenic Disease; Male; Ointments; Psoriasis; Sodium Chloride Symporter Inhibitors

The present experiments were conducted to compare the relative hypercalciuric and hypercalcemic activities of 1,24-dihydroxyvitamin D(2) [1,24-(OH)(2)D(2)], 1,24-dihydroxyvitamin D(3) [1, 24-(OH)(2)D(3)], and 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in 7-week-old rats. The rats were dosed orally with each sterol for 7 days at a rate of 1 ng/g body weight/day. We also monitored the effect of the three compounds on the induction of mRNA for CaATPase and for 25-hydroxyvitamin D-24-hydroxylase in the kidney and intestine, on plasma vitamin D metabolite levels, and on the capacity to evoke modification in the vitamin D receptor/retinoic acid X receptor (VDR/RXR) heterodimer conformation. Plasma calcium was elevated in the rats treated with 1,24-(OH)(2)D(3) and 1, 25-(OH)(2)D(3), but not in the 1,24-(OH)(2)D(2)-dosed rats. Urinary calcium was elevated significantly (relative to controls) in all groups. The order of hypercalciuric activity was 1,25-(OH)(2)D(3) >/= 1,24-(OH)(2)D(3) >/= 1,24-(OH)(2)D(2) > control. Duodenal plasma membrane calcium ATPase (PMCA) mRNA was elevated to a similar extent in all groups relative to controls. Duodenal 24-hydroxylase mRNA was elevated in all groups relative to controls; however, the elevations were significantly higher in the 1,24-(OH)(2)D(3) and 1, 25-(OH)(2)D(3) groups compared with the 1,24-(OH)(2)D(2) group. Kidney 24-hydroxylase also was elevated significantly in the 1, 24-(OH)(2)D(3)- and 1,25-(OH)(2)D(3)-treated rats but not in the 1, 24-(OH)(2)D(2)-treated rats. Recombinant human vitamin D receptor (hVDR) extracts were incubated with saturating concentrations of 1, 24-(OH)(2)D(2), 1,24-(OH)(2)D(3), and 1,25-(OH)(2)D(3) and subsequently analyzed by electrophoretic mobility shift assay (EMSA). Overall binding was comparable for all metabolites; however, the 1, 24-(OH)(2)D(2) complex exhibited distinctly altered mobility relative to 1,24-(OH)(2)D(3) and 1,25-(OH)(2)D(3), suggestive of an effect on hVDR/hRXR conformation. These data suggest that 1, 24-(OH)(2)D(2) is not as potent as either of the vitamin D(3) sterols at affecting hypercalcemia or hypercalciuria in young growing rats; however, 1,24-(OH)(2)D(2) can evoke other biological responses similar to the vitamin D(3) sterols. These different responses may be related to the alterations in conformation state of the hVDR/hRXR heterodimer.

Topics: Analysis of Variance; Animals; Binding, Competitive; Calcitriol; Calcium; Dihydroxycholecalciferols; Ergocalciferols; Hypercalcemia; Male; Rats; Receptors, Calcitriol; RNA, Messenger; Vitamin D

1 alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is known to be a hormonally active form of vitamin D3 in the regulation of intracellular and extracellular calcium levels and of differentiation of myeloid cells and epidermal keratinocytes. We found that 1 alpha,24(R)-dihydroxyvitamin D3 (1,24(OH)2D3), a novel synthetic derivative of vitamin D3, is also active in regulating the differentiation of epidermal keratinocytes. 1,24(OH)2D3 had the same affinity as 1,25(OH)2D3 for a receptor isolated from the epidermis of newborn mice. The incubation of mouse epidermal keratinocytes with 1,24(OH)2D3 induced their differentiation in a time- and dose-dependent manner, as determined by the formation of a cornified envelope and an increase in the activity of transglutaminase. 1,24(OH)2D3 inhibited DNA synthesis of epidermal keratinocytes and also increased their cytosolic calcium level. These effects of 1,24(OH)2D3 were similar to, or rather more than, those of physiologically active 1,25(OH)2D3. However, 1,24(OH)2D3 was found to cause less hypercalcemia than 1,25(OH)2D3 when administrated intravenously to rats, suggesting its possible therapeutic value in psoriasis.

Topics: Animals; Cell Differentiation; Cells, Cultured; Dihydroxycholecalciferols; Humans; Hypercalcemia; Keratinocytes; Psoriasis; Rats; Receptors, Calcitriol; Receptors, Steroid

A lipid indistinguishable from 1,24(R)-dihydroxyvitamin D3 [1,24(R)-(OH)2D3] was found in serum and tumor extracts from a hypercalcemic patient with a small cell carcinoma of the lung. The lipid comigrated with authentic 1,24(R)-(OH)2D3 on high performance liquid chromatography using both straight and reverse phase columns and competed with tritiated 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3)] for binding to intestinal 1,25-(OH)2D3 receptor. Increasing doses of the lipid factor from tumor and authentic 1,24(R)-(OH)2D3 gave parallel responses in a bone resorption assay, as assessed by 45Ca release from prelabeled mouse calvaria. The lipid factor from the patient's serum and authentic 1,24(R)-(OH)2D3 had identical biological activities in the receptor binding and bone resorption assays. In addition, the mechanisms of action of this lipid factor and 1,24(R)-(OH)2D3 were indistinguishable. Bone resorption by both was inhibited by calcitonin, and neither the lipid factor nor authentic 1,24(R)-(OH)2D3 affected cAMP content in osteoblast-like bone cells derived from mouse calvaria. The estimated concentrations of the 1,24(R)-(OH)2D3-like lipid, expressed as 1,24(R)-(OH)2D3 were 11 ng/g tumor wet wt by the receptor binding assay and 9.2 ng/g tumor wet wt by the bone resorption assay. The mean serum concentration was 1.4 +/- 0.3 (+/- SD) ng/ml (n = 3) by the receptor binding assay. No activity was detected in either bioassay when extracts of nontumor tissues from this patient or tumor extracts and sera from one hypercalcemic and four normocalcemic cancer patients were tested. The mean serum 1,25-(OH)2D level was low (6.4 +/- 0.5 pg/ml; n = 2), and serum 1,24(R),25-(OH)3D in this patient was high (103 pg/ml) compared to normocalcemic cancer patients, in whom the mean serum 1,25-(OH)2D level was 27 +/- 12 pg/ml (n = 4) and the 1,24(R),25(OH)3D level was 28 +/- 1.3 pg/ml (n = 4). Thus, the 1,24(R)-(OH)2D3-like lipid may be a substrate for metabolic conversion to 1,24(R),25-(OH)3D in vivo. These results provide evidence for the presence of a novel metabolite of vitamin D3, 1,24(R)-(OH)2D3. Detection of this bone-resorbing lipid in both tumor and serum suggests, but does not prove, that the tumor secreted this bioactive lipid into the circulation and that the high level of circulating bone-resorbing lipid was related to the hypercalcemia in this patient.

Topics: Animals; Bone and Bones; Bone Resorption; Calcium; Carcinoma, Small Cell; Chromatography, High Pressure Liquid; Cyclic AMP; Dihydroxycholecalciferols; Ergocalciferols; Humans; Hypercalcemia; In Vitro Techniques; Lipids; Lung Neoplasms; Male; Mice; Middle Aged; Paraneoplastic Endocrine Syndromes; Radioligand Assay