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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.