Comparison of the relative effects of 1,24-dihydroxyvitamin D-2 [1,24-(OH)(2)D-2], 1,24-dihydroxyvitamin D-3 [1,24-(OH)(2)D-3], and 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] on selected vitamin D-regulated events in the rat

Citation
R. Horst et al., Comparison of the relative effects of 1,24-dihydroxyvitamin D-2 [1,24-(OH)(2)D-2], 1,24-dihydroxyvitamin D-3 [1,24-(OH)(2)D-3], and 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] on selected vitamin D-regulated events in the rat, BIOCH PHARM, 60(5), 2000, pp. 701-708
Citations number
25
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
00062952 → ACNP
Volume
60
Issue
5
Year of publication
2000
Pages
701 - 708
Database
ISI
SICI code
0006-2952(20000901)60:5<701:COTREO>2.0.ZU;2-5
Abstract
The present experiments were conducted to compare the relative hypercalciur ic and hypercalcemic activities of 1,24-dihydroxyvitamin D-2 [1,24-(OH)(2)D -2], 1,24-dihydroxyvitamin D-3 [1,24-(OH)(2)D-3], and 1,25 dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] 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 monitor ed 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 modificati on in the vitamin D receptor/retinoic acid X receptor (VDR/RXR) heterodimer conformation. Plasma calcium was elevated in the rats treated with 1,24 (O H)(2)D-3 and 1,25-(OH)(2)D-3, but not in the 1,24- (OH)(2)D-2-dosed rats. U rinary calcium was elevated significantly (relative to controls) in ail gro ups. The order of hypercalciuric activity was 1,25-(OH)(2)D-3 greater than or equal to 1,24-(OH)(2)D-3 greater than or equal to 1,24-(OH)(2)D-2 > cont rol. 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 elevatio ns were significantly higher in the 1,24-(OH)(2)D-3 and 1,25-(OH)(2)D-3 gro ups compared with the 1,24-(OH)(2)D-2 group. Kidney 24-hydroxylase also was elevated significantly in the 1,24-(OH)(2)D-3- and 1,25-(OH)(2)D-3-treated rats but not in the 1,24-(OH)(2)D-2-treated rats. Recombinant human vitami n D receptor (hVDR) extracts were incubated with saturating concentrations of 1,24-(OH)(2)D-2, 1,24-(OH)(2)D-3, and 1,25-(OH)(2)D-3 and subsequently a nalyzed by electrophoretic mobility shift assay (EMSA). Overall binding was comparable for all metabolites; however, the 1,24 (OH)(2)D-2 complex exhib ited distinctly altered mobility relative to 1,24-(OH)(2)D-3 and 1,25-(OH)( 2)D-3, suggestive of an effect on hVDR/hRXR conformation. These data sugges t that 1,24-(OH)(2)D-2 is not as potent as either of the vitamin D-3 sterol s at affecting hypercalcemia or hypercalciuria in young growing rats; howev er, 1,24-(OH)(2)D-2 can evoke other biological responses similar tc, the vi tamin D-3 sterols. These different responses may be related to the alterati ons in conformation state of the hVDR/hRXR heterodimer. BIOCHEM PHARMACOL 6 0;5:701-705, 2000. (C) 2000 Elsevier Science Inc.