1-25-dihydroxyvitamin-d3-26-23-lactone and Vitamin-D-Deficiency

Synthesis of 1,25(OH)2D3 is controlled by numerous factors. The major ones, however, are the circulating amounts of parathyroid hormone (the secretion of which is stimulated by low serum calcium), serum or extracellular fluid phosphorus concentrations, circulating levels of 1,25(OH)2D3 itself, and perhaps serum calcium directly. Many of the other factors noted have effects in vitro only or effects that are observed inconsistently or in one species only. Thus, in low-calcium states, 1,25(OH)2D3 synthesis increases because of increased parathyroid hormone activity. Parathyroid hormone may stimulate 1,25(OH)2D3 synthesis directly or via alterations (a decrease) in serum phosphorus or both. Low serum phosphorus will stimulate 1,25(OH)2D3 synthesis independent of parathyroid hormone levels. Low serum calcium may directly stimulate 25(OH)D3 1 alpha-hydroxylase activity independently of parathyroid hormone. In general terms the vitamin D-endocrine system tends to correct abnormalities in calcium and phosphorus homeostasis. The further metabolism of 1,25(OH)2D3 to other metabolites appears to be mainly a degradative or excretory process. Currently there is no evidence that 1,25(OH)2D3 must itself be altered to other metabolites prior to inducing intestinal calcium transport or bone mobilization. The processes involved in the excretion of 1,25(OH)2D3, such as side-chain oxidation and biliary excretion, are not regulated by serum calcium, phosphorus, or 1,25(OH)2D3 levels. The biliary excretion pathway is also unsaturable over a very wide range and not regulated by calcium, phosphorus, or vitamin D3. Therefore these processes, which account for a large part of the metabolism of 1,25(OH)2D3, are largely unregulated by factors that control the synthesis of 1,25(OH)2D3 and regulate the formation of other calcium-controlling hormones. Other processes involved in the metabolism of 1,25(OH)2D3, such as 24-hydroxylation and 26-hydroxylation, occur in normocalcemic and normophosphatemic states. 24-Hydroxylation is also induced by 1,25(OH)2D3, which benefits the organism, because excessive 1,25(OH)2D3 in various tissues can be altered to a less active metabolite, 1,24,25(OH)3D3. Although there is still no evidence concerning the regulation of C-24 oxidation by dietary calcium and phosphorus levels, the fact that this process is induced by 1,25(OH)2D3 suggests that the metabolic pathway functions in much the same manner as the 24-hydroxylation pathway. The formation of 1,25(

Topics: Animals; Bile; Bone and Bones; Calcitriol; Chickens; Cholecalciferol; Half-Life; Humans; Hydroxylation; Intestinal Mucosa; Liver; Oxidation-Reduction; Rats; Vitamin D Deficiency

Topics: Animals; Bone Morphogenetic Proteins; Calcitriol; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Female; Insulin-Like Growth Factor I; Mice; Osteogenesis; Osteoporosis; Ovariectomy; Proteins; Rats; Rats, Wistar; Time Factors; Vitamin D; Vitamin D Deficiency

The biological activity of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone, and three intermediate metabolites of the lactone in vivo and in vitro was comparatively examined. The three intermediate metabolites, 1 alpha,25(R)26(OH)3D3, 1 alpha,23(S)25(R)26(OH)4D3, and 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactol, stimulated increases, as did 1 alpha,25(OH)2D3, in intestinal calcium transport and serum calcium level in vitamin D-deficient rats fed a low-calcium diet. On the other hand, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone increased the calcium transport but decreased the serum calcium level. 1 alpha,25(OH)2D3,23(S)25(R)-Lactone and the other three metabolites stimulated multinucleate cell formation from hematopoietic blast cells in a manner correlated with their binding affinities for the 1 alpha,25(OH)2D3 receptor. But 23(S)25(R)-lactone did not show any inhibitory effect on the multinucleate cell formation induced by 1 alpha,25(OH)2D3 in contrast to the results obtained from unfractionated marrow cultures. Conditioned medium obtained from 23(S)25(R)-lactone-treated MC3T3-E1 cells inhibited the formation, probably by the action of some inhibitory factors elaborated by the cells treated with the lactone, whereas conditioned medium obtained from 1 alpha,25(OH)2D3 or other metabolite-treated MC3T3-E1 cells stimulated the formation. These findings suggest that 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone might inhibit bone resorption through an inhibition of osteoclastic cell formation and that other vitamin D3 metabolites stimulate bone resorption by development of new osteoclastic cells in addition to indirect osteoclast activation.

Topics: Animals; Biotransformation; Bone and Bones; Calcitriol; Calcium; Cells, Cultured; Duodenum; Intestinal Absorption; Kinetics; Male; Muscle, Smooth; Rats; Rats, Inbred Strains; Reference Values; Structure-Activity Relationship; Vitamin D Deficiency

All four possible diastereoisomers of 1 alpha,25-dihydroxycholecalciferol-26,23-lactone (1 alpha,25-(OH)2D3-26,23-lactone) were chemically synthesized and were compared to 1 alpha,25-dihydroxycholecalciferol (1 alpha,25(OH)2D3) in terms of their stimulation, in vivo, of intestinal calcium transport and mobilization of calcium from bone in vitamin D-deficient rats (the two classic vitamin D-mediated responses), and their relative binding to the chick intestinal cytosol receptor for 1 alpha,25-(OH)2D3. The receptor binding affinity results are expressed as relative competitive index (RCI), where the RCI is defined as 100 for 1 alpha,25(OH)2D3. The RCI obtained for 23(S)25(S)-1 alpha,25(OH)2D3-26,23-lactone was 7.90, for 23(R)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 2.27, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 0.17, for 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone 0.22 and for the in vivo produced 1 alpha,25(OH)2D3-26,23-lactone the RCI was only 0.17. Also the four diastereoisomers of 1 alpha,25(OH)2D3-26,23-lactone all stimulated intestinal calcium transport, reaching a maximum 8 h after administration. Compared with the stimulation of intestinal calcium transport by 1 alpha,25(OH)2D3, 23(S)25(S)-1 alpha,25(OH)2D3-26,23-lactone was 1/4 as effective, 23(R)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 1/20 as effective, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 1/74 as effective and 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone was 1/53 as effective. Similarly, 23(S)25(S)-1 alpha,25(OH)2D3-26,23-lactone and 23(R)25(R)-1 alpha,25(OH)2D3-26,23-lactone were estimated to be 3 and 20 times less active than 1 alpha,25-(OH)2D3 in elevation of serum calcium. However, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone and 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone decreased the serum calcium levels 24 h after administration. 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone reduced serum calcium concentrations to a greater extent than 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone. These results indicate that the biological activities of the diastereoisomers of 1 alpha,25(OH)2D3-26,23-lactone were quite different among four stereochemical configurations.

Topics: Animals; Binding, Competitive; Biological Transport; Bone and Bones; Calcitriol; Calcium; Chickens; Intestinal Absorption; Male; Rats; Rats, Inbred Strains; Receptors, Calcitriol; Receptors, Steroid; Stereoisomerism; Vitamin D Deficiency

1 alpha,25-Dihydroxyvitamin D3-26,23-lactone [1 alpha,25(OH)2D3-26,23-lactone] was compared to 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] in terms of their stimulation, in vivo, of intestinal calcium transport and mobilization of calcium from bone in the rat (the two classic vitamin D-mediated responses), and their relative binding to the chick intestinal receptor for 1 alpha,25(OH)2D3, 1 alpha,25-(OH)2D3-26,23-lactone was found to be only one-thirtieth as active as 1 alpha,25-(OH)2D3 in the stimulation of intestinal calcium transport and was found to mediate a significant reduction in the steady-state serum calcium levels. Associated with the reduction in serum calcium was a significant increase in urinary calcium excretion for 24 h after the administration of the steroid. Prior administration of 1 alpha,25(OH)2D3-26,23-lactone partially blocked the actions of a subsequently administered dose of 1 alpha,25(OH)2D3 in increasing serum calcium levels, but did not affect the action of 1 alpha,25(OH)2D3 in stimulating intestinal calcium transport. The binding affinity of 1 alpha,25(OH)2D3-26,23-lactone to the chick intestinal cytosol receptor protein was observed to be 670 times lower than that of 1,25-(OH)2D3 which indicates that perturbation of the 25-hydroxylated side chain by formation of the 26,23-lactone causes a significant reduction in ligand affinity for the receptor.

Topics: Animals; Biological Transport, Active; Calcitriol; Calcium; Duodenum; Intestinal Absorption; Kinetics; Male; Rats; Rats, Inbred Strains; Receptors, Calcitriol; Receptors, Steroid; Vitamin D Deficiency