Nephrol Dial Transplant (2000) 15: 1943-1949
© 2000 European Renal Association-European Dialysis and Transplant Association
Potent suppression of the parathyroid glands by hydroxylated metabolites of dihydrotachysterol2
1 Departments of Nephrology and 2 Clinical Biochemistry, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK and 3 Leo Pharmaceuticals, Ballerup, Denmark
Background. Dihydrotachysterol2, a licensed pharmaceutical, is hydroxylated to 25-hydroxydihydrotachysterol2 (25(OH)DHT2) and 1
,25-dihydroxydihydrotachysterol2 (1,25(OH)2DHT2) 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)DHT2 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 1,25(OH)2DHT2 and 25(OH)DHT2 required higher concentrations to suppress PTH equally. We were unable to detect metabolism of 25(OH)DHT2 to 1,25(OH)2DHT2 in vitro. In rats, a single dose of 0.5 µg/rat of calcitriol increased ionized calcium at 30 and 40 h (statistically significant at 48 h). 50 µg of OCT and 1,25(OH)2DHT2 did not cause significant hypercalcaemia at 48 h, although 1,25(OH)2DHT2 caused hypercalcaemia at 30 h. In contrast, 50 µg of 25(OH)DHT2 caused hypercalcaemia at 48 h but not at 30 h. Five daily doses of 0.001 µg/rat of calcitriol caused a significant rise in calcium and a 50% fall in PTH. OCT and 1,25(OH)2DHT2 at 0.025 and 0.5 µg/rat respectively caused similar suppression of PTH but without hypercalcaemia.
Conclusion. 1,25(OH)2DHT2 and 25(OH)DHT2 are potent suppressors of PTH in vitro and in vivo. 25(OH)DHT2 may be active by virtue of its pseudo-1-hydroxyl group. Hypercalcaemia caused by a single dose of 1,25(OH)2DHT2 appeared to be more transient than calcitriol. Five daily doses of 1,25(OH)2DHT2 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, 1,25(OH)2DHT2 can dissociate calcaemic actions from parathyroid-suppressing actions in a manner that may be therapeutically useful.
Keywords: 1,25(OH)2DHT2; 25(OH)DHT2; calcitriol; hypercalcaemia; ionized calcium; parathyroid hormone
Correspondence and offprint requests to: Dr J. Cunningham, Department of Renal Medicine and Transplantation, The Royal London Hospital, Whitechapel, London E1 1BB, UK.