The vitamin D prodrugs 1α(OH)D2, 1α(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells

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 alpha(OH)D-3, a vitamin D prodrug, inhibited PTH secretion in cultured bovine parathyroid cells, but it was unclear whether 1 alpha(OH)D-3 itself or an active metabolite produced this inhibition. Methods. We determined the effectiveness of the vitamin D prodrugs 1 alpha(OH)D-3, 1 alpha(OH)D-2 and 1 alpha(OH)-24(R)-methyl-25-ene-D-2 (BCI-210) at inhibiting PTH secretion in bovine parathyroid cell cultures, and examined the metabolism of [H-3]1 alpha(OH)D-2 in these cells. Results. All three prodrugs suppressed PTH secretion with approximately 10% of the activity of 1,25(OH)(2)D-3; much higher activity than expected based on the VDR affinities of these prodrugs (0.25% of 1,25(OH)(2)D-3). Parathyroid cells activated [H-3]1 alpha(OH)D-2 to both 1,25(OH)(2)D-2 and 1,24(OH)(2)D-2. 1,24(OH)(2)D-2 was detectable at 4 h, increased to a maximum at 8 h, and then decreased. In contrast, 1,25(OH)(2)D-2 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 mu M) reduced 1 alpha(OH)D-2 metabolism to below detectable levels, but did not significantly affect suppression of PTH by 1 alpha(OH)D-2. Conclusions. The vitamin D prodrugs 1 alpha(OH)D-3, 1 alpha(OH)D-2 and BCI-210 suppressed PTH production by cultured parathyroid cells. The ability of 1 alpha(OH)D-2 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.