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The vitamin D prodrugs 1alpha(OH)D2, 1alpha(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells.
Nephrol Dial Transplant. 2006 Mar; 21(3):644-50.ND

Abstract

BACKGROUND

Active vitamin D compounds are widely used in the treatment of secondary hyperparathyroidism associated with renal failure. These compounds reduce PTH secretion through vitamin D receptor (VDR)-dependent repression of PTH gene transcription. In previous studies, 1alpha(OH)D3, a vitamin D prodrug, inhibited PTH secretion in cultured bovine parathyroid cells, but it was unclear whether 1alpha(OH)D3 itself or an active metabolite produced this inhibition.

METHODS

We determined the effectiveness of the vitamin D prodrugs 1alpha(OH)D3, 1alpha(OH)D2 and 1alpha(OH)-24(R)-methyl-25-ene-D2 (BCI-210) at inhibiting PTH secretion in bovine parathyroid cell cultures, and examined the metabolism of [3H]1alpha(OH)D2 in these cells.

RESULTS

All three prodrugs suppressed PTH secretion with approximately 10% of the activity of 1,25(OH)2D3; much higher activity than expected based on the VDR affinities of these prodrugs (0.25% of 1,25(OH)2D3). Parathyroid cells activated [3H]1alpha(OH)D2 to both 1,25(OH)2D2 and 1,24(OH)2D2. 1,24(OH)2D2 was detectable at 4 h, increased to a maximum at 8 h, and then decreased. In contrast, 1,25(OH)2D2 levels increased linearly with time, suggesting the presence of constitutively active vitamin D-25-hydroxylase not previously reported in parathyroid cells. The cytochrome P-450 inhibitor ketoconazole (50 microM) reduced 1alpha(OH)D2 metabolism to below detectable levels, but did not significantly affect suppression of PTH by 1alpha(OH)D2.

CONCLUSIONS

The vitamin D prodrugs 1alpha(OH)D3, 1alpha(OH)D2 and BCI-210 suppressed PTH production by cultured parathyroid cells. The ability of 1alpha(OH)D2 to reduce PTH despite inhibition of its metabolism suggests a direct action of this 'prodrug' on the parathyroid gland, but the mechanism underlying this activity is not yet known.

Authors+Show Affiliations

Renal Division, Washington University School of Medicine, St. Louis, MO 63110, USA. abrown@imgate.wustl.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16221703

Citation

Brown, Alex J., et al. "The Vitamin D Prodrugs 1alpha(OH)D2, 1alpha(OH)D3 and BCI-210 Suppress PTH Secretion By Bovine Parathyroid Cells." Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, vol. 21, no. 3, 2006, pp. 644-50.
Brown AJ, Ritter CS, Knutson JC, et al. The vitamin D prodrugs 1alpha(OH)D2, 1alpha(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells. Nephrol Dial Transplant. 2006;21(3):644-50.
Brown, A. J., Ritter, C. S., Knutson, J. C., & Strugnell, S. A. (2006). The vitamin D prodrugs 1alpha(OH)D2, 1alpha(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells. Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, 21(3), 644-50.
Brown AJ, et al. The Vitamin D Prodrugs 1alpha(OH)D2, 1alpha(OH)D3 and BCI-210 Suppress PTH Secretion By Bovine Parathyroid Cells. Nephrol Dial Transplant. 2006;21(3):644-50. PubMed PMID: 16221703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The vitamin D prodrugs 1alpha(OH)D2, 1alpha(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells. AU - Brown,Alex J, AU - Ritter,Cynthia S, AU - Knutson,Joyce C, AU - Strugnell,Stephen A, Y1 - 2005/10/12/ PY - 2005/10/14/pubmed PY - 2006/6/30/medline PY - 2005/10/14/entrez SP - 644 EP - 50 JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JO - Nephrol. Dial. Transplant. VL - 21 IS - 3 N2 - BACKGROUND: Active vitamin D compounds are widely used in the treatment of secondary hyperparathyroidism associated with renal failure. These compounds reduce PTH secretion through vitamin D receptor (VDR)-dependent repression of PTH gene transcription. In previous studies, 1alpha(OH)D3, a vitamin D prodrug, inhibited PTH secretion in cultured bovine parathyroid cells, but it was unclear whether 1alpha(OH)D3 itself or an active metabolite produced this inhibition. METHODS: We determined the effectiveness of the vitamin D prodrugs 1alpha(OH)D3, 1alpha(OH)D2 and 1alpha(OH)-24(R)-methyl-25-ene-D2 (BCI-210) at inhibiting PTH secretion in bovine parathyroid cell cultures, and examined the metabolism of [3H]1alpha(OH)D2 in these cells. RESULTS: All three prodrugs suppressed PTH secretion with approximately 10% of the activity of 1,25(OH)2D3; much higher activity than expected based on the VDR affinities of these prodrugs (0.25% of 1,25(OH)2D3). Parathyroid cells activated [3H]1alpha(OH)D2 to both 1,25(OH)2D2 and 1,24(OH)2D2. 1,24(OH)2D2 was detectable at 4 h, increased to a maximum at 8 h, and then decreased. In contrast, 1,25(OH)2D2 levels increased linearly with time, suggesting the presence of constitutively active vitamin D-25-hydroxylase not previously reported in parathyroid cells. The cytochrome P-450 inhibitor ketoconazole (50 microM) reduced 1alpha(OH)D2 metabolism to below detectable levels, but did not significantly affect suppression of PTH by 1alpha(OH)D2. CONCLUSIONS: The vitamin D prodrugs 1alpha(OH)D3, 1alpha(OH)D2 and BCI-210 suppressed PTH production by cultured parathyroid cells. The ability of 1alpha(OH)D2 to reduce PTH despite inhibition of its metabolism suggests a direct action of this 'prodrug' on the parathyroid gland, but the mechanism underlying this activity is not yet known. SN - 0931-0509 UR - https://www.unboundmedicine.com/medline/citation/16221703/The_vitamin_D_prodrugs_1alpha_OH_D2_1alpha_OH_D3_and_BCI_210_suppress_PTH_secretion_by_bovine_parathyroid_cells_ L2 - https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfi186 DB - PRIME DP - Unbound Medicine ER -