1-25-dihydroxyvitamin-d3-26-23-lactone and calcifediol-lactone

The binding of the natural and unnatural diastereoisomers 25-hydroxyvitamin D3-26,23-lactone and 1,25 dihydroxyvitamin D3-26,23-lactone to the vitamin D-binding protein (DBP) and 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] chick intestinal receptor have been investigated. Also, the biological activities, under in vivo conditions, of these compounds, in terms of intestinal calcium absorption (ICA) and bone calcium mobilization (BCM), in the chick are reported. The presence of the lactone ring in the C23-C26 position of the seco-steroid side chain increased two to three times the ability of both 25(OH)D3 and 1,25(OH)2D3 to displace 25(OH)[3H]D3 from the D-binding protein; however, the DBP could not distinguish between the various diastereoisomers. In contrast, the unnatural form (23R,25S) of the 25-hydroxy-lactone was found to be 10-fold more potent than the natural form, and the unnatural (23R,25S)1,25(OH)2D3-26,23-lactone three times more potent than the natural 1,25-dihydroxy-lactone in displacing 1,25(OH)2[3H]D3 from its intestinal receptor. While studying the biological activity of these lactone compounds, it was found that the natural form of the 25-hydroxy-lactone increased the intestinal calcium absorption 48 h after injection (16.25 nmol), while bone calcium mobilization was decreased by the same dose of the 25-hydroxy-lactone. The 1,25-dihydroxyvitamin D3-26,23-lactone in both its natural and unnatural forms was found to be active in stimulating ICA and BCM. These results suggest that the 25-hydroxy-lactone has some biological activity in the chick and that 1,25(OH)2D3-26,23-lactone can mediate ICA and BCM biological responses, probably through an interaction with 1,25-(OH)2D3 specific receptors in these target tissues.

Topics: Animals; Binding, Competitive; Bone and Bones; Calcifediol; Calcitriol; Calcium; Chickens; Cytosol; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Protein Binding; Receptors, Calcitriol; Receptors, Steroid; Stereoisomerism; Vitamin D-Binding Protein

Topics: Animals; Calcifediol; Calcitriol; Chickens; Chromatography, High Pressure Liquid; Hydroxycholecalciferols; Male; Mass Spectrometry; Molecular Conformation; Rats; Rats, Inbred Strains; Spectrophotometry, Infrared; Stereoisomerism

Labeled 25-hydroxyvitamin D3-26,23-lactone was isolated from the serum of vitamin D-repleted rats given [3 alpha-3H]-25-hydroxyvitamin D324 hr prior to sacrifice. The metabolite was identified by cochromatography with the authentic lactone on straight-phase and reversed-phase high-performance liquid chromatography. Production of the lactone was abolished by nephrectomy indicating that the kidney is the site of synthesis. Homogenate of kidneys from chickens given large doses of vitamin D can carry out in vitro production of the lactone from 25-hydroxyvitamin D3. When 1 alpha, 25-dihydroxyvitamin D3 was used as substrate, this system produced only traces of a compound believed to be 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone. However, incubation of rachitic chicken kidney homogenates with 25-hydroxyvitamin D3-26,23-lactone produced substantial amounts of a compound that has been identified by mass spectrometry as 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone. Thus, the development of a functional group on C-26 and eventual lactone formation takes place in kidney by a system acting on 25-hydroxyvitamin D3.

Topics: Animals; Calcifediol; Calcitriol; Chickens; Dihydroxycholecalciferols; Hydroxycholecalciferols; Kidney; Lactones; Male; Rats