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Comparison of the Relative Effects of 1,24-Dihydroxyvitamin D2 [1,24-(OH)2D2], 1,24-Dihydroxyvitamin D3 [1,24-(OH)2D3], and 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] on Selected Vitamin D-Regulated Events in the Rat

Horst, R., Prapong, S., Reinhardt, T., Koszewski, N., Knutson, J., Bishop, C.
Biochemical pharmacology 2000 v.60 no.5 pp. 701
calcitriol, vitamin D, Ca2-transporting ATPase, cytochrome P-450, messenger RNA, gene expression regulation, receptors, rats, animal models, blood plasma, urine, calcium, duodenum, plasma membrane, hypercalcemia, vitamin metabolism, protein binding, human health
The present experiments were conducted to compare the relative hypercalciuric and hypercalcemic activities of 1,24-dihydroxyvitamin D2 [1,24-(OH)2D2], 1,24-dihydroxyvitamin D3 [1,24-(OH)2D3], and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in 7-week-old rats. The rats were dosed orally with each sterol for 7 days at a rate of 1 ng/g body weight/day. We also monitored the effect of the three compounds on the induction of mRNA for CaATPase and for 25-hydroxyvitamin D-24-hydroxylase in the kidney and intestine, on plasma vitamin D metabolite levels, and on the capacity to evoke modification in the vitamin D receptor/retinoic acid X receptor (VDR/RXR) heterodimer conformation. Plasma calcium was elevated in the rats treated with 1,24-(OH)2D3 and 1,25-(OH)2D3, but not in the 1,24-(OH)2D2-dosed rats. Urinary calcium was elevated significantly (relative to controls) in all groups. The order of hypercalciuric activity was 1,25-(OH)2D3 >= 1,24-(OH)2D3 >= 1,24-(OH)2D2 > control. Duodenal plasma membrane calcium ATPase (PMCA) mRNA was elevated to a similar extent in all groups relative to controls. Duodenal 24-hydroxylase mRNA was elevated in all groups relative to controls; however, the elevations were significantly higher in the 1,24-(OH)2D3 and 1,25-(OH)2D3 groups compared with the 1,24-(OH)2D2 group. Kidney 24-hydroxylase also was elevated significantly in the 1,24-(OH)2D3- and 1,25-(OH)2D3-treated rats but not in the 1,24-(OH)2D2-treated rats. Recombinant human vitamin D receptor (hVDR) extracts were incubated with saturating concentrations of 1,24-(OH)2D2, 1,24-(OH)2D3, and 1,25-(OH)2D3 and subsequently analyzed by electrophoretic mobility shift assay (EMSA). Overall binding was comparable for all metabolites; however, the 1,24-(OH)2D2 complex exhibited distinctly altered mobility relative to 1,24-(OH)2D3 and 1,25-(OH)2D3, suggestive of an effect on hVDR/hRXR conformation. These data suggest that 1,24-(OH)2D2 is not as potent as either of the vitamin D3 sterols at affecting hypercalcemia or hypercalciuria in young growing rats; however, 1,24-(OH)2D2 can evoke other biological responses similar to the vitamin D3 sterols. These different responses may be related to the alterations in conformation state of the hVDR/hRXR heterodimer.