NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(3):644-650; doi:10.1093/ndt/gfi186
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
The vitamin D prodrugs 1
(OH)D2, 1(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells
1 Renal Division, Washington University School of Medicine, St Louis, MO and 2 Preclinical Research, Bone Care International, Middleton, WI, USA
Correspondence and offprint requests to: Alex J. Brown, PhD, Renal Division, Washington University School of Medicine, Box 8126, 660 S. Euclid, St. Louis, MO 63110. Email: abrown{at}imgate.wustl.edu
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, 1
(OH)D3, a vitamin D prodrug, inhibited PTH secretion in cultured bovine parathyroid cells, but it was unclear whether 1(OH)D3 itself or an active metabolite produced this inhibition.
Methods. We determined the effectiveness of the vitamin D prodrugs 1(OH)D3, 1(OH)D2 and 1(OH)-24(R)-methyl-25-ene-D2 (BCI-210) at inhibiting PTH secretion in bovine parathyroid cell cultures, and examined the metabolism of [3H]1(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]1(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 µM) reduced 1(OH)D2 metabolism to below detectable levels, but did not significantly affect suppression of PTH by 1(OH)D2.
Conclusions. The vitamin D prodrugs 1(OH)D3, 1(OH)D2 and BCI-210 suppressed PTH production by cultured parathyroid cells. The ability of 1(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.
Keywords: BCI-210; 1-hydroxyvitamin D2; 1-hydroxyvitamin D3; ketoconazole; parathyroid hormone; vitamin D
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