Potent suppression of the parathyroid glands by hydroxylated metabolites of dihydrotachysterol(2).

Background: Dihydrotachysterol(2), a licensed pharmaceutical, is hydroxylated to 25-hydroxydihydrotachysterol(2) (25(OH)DHT(2)) and 1 alpha,25-dihydroxydihydrotachysterol(2) (1 alpha,25(OH)(2)DHT(2)) in man. We have compared the biological activity of these metabolites with calcitriol and the 'non-calcaemic' analogue, 22-oxacalcitriol (OCT) in bovine parathyroid cell cultures and in rats.

Methods: The effect of each sterol on parathyroid hormone (PTH) secreted by primary bovine parathyroid cells was measured. High-performance liquid chromotography and gas chromotography-mass spectrometry were used to investigate in vitro 25(OH)DHT(2) metabolism. Rats were given a single intraperitoneal injection or five daily injections of each sterol, and changes in ionized calcium and PTH were measured.

Results: In vitro, all sterols suppressed PTH significantly. Calcitriol and OCT were of similar potency, but 1 alpha, 25(OH)(2)DHT(2) and 25(OH)DHT(2) required higher concentrations to suppress PTH equally. We were unable to detect metabolism of 25(OH)DHT(2) to 1 alpha,25(OH)(2)DHT(2) in vitro. In rats, a single dose of 0.5 microg/rat of calcitriol increased ionized calcium at 30 and 40 h (statistically significant at 48 h). 50 microg of OCT and 1 alpha,25(OH)(2)DHT(2) did not cause significant hypercalcaemia at 48 h, although 1 alpha,25(OH)(2)DHT(2) caused hypercalcaemia at 30 h. In contrast, 50 microg of 25(OH)DHT(2) caused hypercalcaemia at 48 h but not at 30 h. Five daily doses of 0.001 microg/rat of calcitriol caused a significant rise in calcium and a 50% fall in PTH. OCT and 1 alpha,25(OH)(2)DHT(2) at 0.025 and 0.5 microg/rat respectively caused similar suppression of PTH but without hypercalcaemia.

Conclusion: 1 alpha,25(OH)(2)DHT(2) and 25(OH)DHT(2) are potent suppressors of PTH in vitro and in vivo. 25(OH)DHT(2) may be active by virtue of its pseudo-1 alpha-hydroxyl group. Hypercalcaemia caused by a single dose of 1 alpha,25(OH)(2)DHT(2) appeared to be more transient than calcitriol. Five daily doses of 1 alpha, 25(OH)(2)DHT(2) and OCT could achieve 50% suppression of PTH without significant increments in ionized calcium. In contrast, suppression of PTH by calcitriol was associated with significant increments in ionized calcium. These data suggest that like OCT, 1 alpha, 25(OH)(2)DHT(2) can dissociate calcaemic actions from parathyroid-suppressing actions in a manner that may be therapeutically useful.