The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion
1,25-Dihydroxyvitamin D (1,25-(OH)2D3) directly suppresses the secretion and synthesis of PTH in vivo and in cell culture. This compound has been used to treat secondary hyperparathyroidism associated with renal failure, but in some patients prolonged treatment with 1,25-(OH)2D3 results in hypercalc...
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Published in | The Journal of clinical investigation Vol. 84; no. 3; pp. 728 - 732 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Ann Arbor, MI
American Society for Clinical Investigation
01.09.1989
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Abstract | 1,25-Dihydroxyvitamin D (1,25-(OH)2D3) directly suppresses the secretion and synthesis of PTH in vivo and in cell culture. This compound has been used to treat secondary hyperparathyroidism associated with renal failure, but in some patients prolonged treatment with 1,25-(OH)2D3 results in hypercalcemia. An analogue of 1,25-(OH)2D3 with little or no calcemic activity, 22-oxacalcitriol (OCT), was recently developed. We confirmed this lack of calcemic activity by acute and chronic administration to normal rats. A single intraperitoneal injection of vehicle (propylene glycol), OCT, or 1,25-(OH)2D3 (1.0 micrograms/rat) increased calcium by 0.32, 0.30, and 1.40 mg/dl, respectively. When rats were given daily injections of vehicle or 0.5 micrograms of either 1,25-(OH)2D3 or OCT for 4 d, calcium did not change in the rats receiving vehicle or OCT, but increased from 8.4 to 11.4 mg/dl in the rats treated with 1,25-(OH)2D3. In primary cultures of bovine parathyroid cells, 10 nM OCT was as active as 10 nM 1,25-(OH)2D3, suppressing PTH release by 33%. This suppression is due, at least in part, to blocking of transcription of the PTH gene. Using a probe prepared by random prime labeling of an Msp I fragment of plasmid PTHm122, we found that a single 40-ng dose of OCT or 1,25-(OH)2D3 depressed PTH mRNA levels by 70-80% by 48 h when compared with vehicle. Thus, OCT is a very effective suppressor of PTH secretion with virtually no calcemic activity. This analogue may be a valuable tool for the treatment of secondary hyperparathyroidism. |
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AbstractList | 1,25-Dihydroxyvitamin D (1,25-(OH)2D3) directly suppresses the secretion and synthesis of PTH in vivo and in cell culture. This compound has been used to treat secondary hyperparathyroidism associated with renal failure, but in some patients prolonged treatment with 1,25-(OH)2D3 results in hypercalcemia. An analogue of 1,25-(OH)2D3 with little or no calcemic activity, 22-oxacalcitriol (OCT), was recently developed. We confirmed this lack of calcemic activity by acute and chronic administration to normal rats. A single intraperitoneal injection of vehicle (propylene glycol), OCT, or 1,25-(OH)2D3 (1.0 micrograms/rat) increased calcium by 0.32, 0.30, and 1.40 mg/dl, respectively. When rats were given daily injections of vehicle or 0.5 micrograms of either 1,25-(OH)2D3 or OCT for 4 d, calcium did not change in the rats receiving vehicle or OCT, but increased from 8.4 to 11.4 mg/dl in the rats treated with 1,25-(OH)2D3. In primary cultures of bovine parathyroid cells, 10 nM OCT was as active as 10 nM 1,25-(OH)2D3, suppressing PTH release by 33%. This suppression is due, at least in part, to blocking of transcription of the PTH gene. Using a probe prepared by random prime labeling of an Msp I fragment of plasmid PTHm122, we found that a single 40-ng dose of OCT or 1,25-(OH)2D3 depressed PTH mRNA levels by 70-80% by 48 h when compared with vehicle. Thus, OCT is a very effective suppressor of PTH secretion with virtually no calcemic activity. This analogue may be a valuable tool for the treatment of secondary hyperparathyroidism. 1,25-Dihydroxyvitamin D (1,25-(OH) sub(2)D sub(3)) directly suppresses the secretion and synthesis of PTH in vivo and in cell culture. This compound has been used to treat secondary hyperparathyroidism associated with renal failure, but in some patients prolonged treatment with 1,25-(OH) sub(2)D sub(3) results in hypercalcemia. An analogue of 1,25-(OH) sub(2)D sub(3) with little or no calcemic activity, 22-oxacalcitriol (OCT), was recently developed. The authors confirmed this lack of calcemic activity by acute and chronic administration to normal rats. OCT is a very effective suppressor of PTH secretion with virtually no calcemic activity. This analogue may be a valuable tool for the treatment of secondary hyperparathyroidism. |
Author | RITTER, C. R FINCH, J. L SLATOPOLSKY, E MURAYAMA, E BROWN, A. J MORRISSEY, J MARTIN, K. J NISHII, Y |
AuthorAffiliation | Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 |
AuthorAffiliation_xml | – name: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 |
Author_xml | – sequence: 1 givenname: A. J surname: BROWN fullname: BROWN, A. J organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 2 givenname: C. R surname: RITTER fullname: RITTER, C. R organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 3 givenname: J. L surname: FINCH fullname: FINCH, J. L organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 4 givenname: J surname: MORRISSEY fullname: MORRISSEY, J organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 5 givenname: K. J surname: MARTIN fullname: MARTIN, K. J organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 6 givenname: E surname: MURAYAMA fullname: MURAYAMA, E organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 7 givenname: Y surname: NISHII fullname: NISHII, Y organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States – sequence: 8 givenname: E surname: SLATOPOLSKY fullname: SLATOPOLSKY, E organization: Washington univ. school medicine, dep. medicine, S. Louis MO 63110, United States |
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SubjectTerms | Animals Biological and medical sciences Calcitriol - administration & dosage Calcitriol - analogs & derivatives Calcitriol - pharmacology Calcium - blood Cells, Cultured Injections, Intraperitoneal Male Medical sciences Miscellaneous Parathyroid Glands - metabolism Parathyroid Glands - secretion Parathyroid Hormone - antagonists & inhibitors Parathyroid Hormone - biosynthesis Parathyroid Hormone - secretion Pharmacology. Drug treatments Protein Precursors - biosynthesis Rats Rats, Inbred Strains RNA, Messenger - biosynthesis |
Title | The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion |
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