Differential effects of 19-nor-1,25-dihydroxyvitamin D(2) and 1,25-dihydroxyvitamin D(3) on intestinal calcium and phosphate transport.
19-Nor-1,25-dihydroxyvitamin D(2) (19-norD(2)) a less calcemic and phosphatemic analog of 1,25-dihydroxyvitamin D (1,25[OH](2)D(3)), is approved for the treatment of secondary hyperparathyroidism in patients with kidney failure. We have previously demonstrated that 19-norD(2) is less active than 1,25(OH)(2)D(3) in stimulating bone resorption. In this study, we compared the potencies of 19-norD(2) and 1,25(OH)(2)D(3) in stimulating net calcium and phosphate absorption in the intestine. Mineral balance was assessed in normal rats during the last 4 days of a 14-day treatment with various daily doses of 19-norD(2) or 1,25(OH)(2)D(3). Calcium absorption increased from 16.5% +/- 7.8% in vehicle-treated rats to 27.5% +/- 7.2% in rats given 10 ng/day 1,25(OH)(2)D(3) and to 21.6% +/- 3.9%, 26.2% +/- 5.5%, and 27.4% +/- 5.1% in rats treated with 10, 50, and 100 ng/day 19-norD(2), respectively. Thus comparable stimulation of calcium transport was attained with 10 ng 1,25(OH)(2)D(3) and 100 ng 19-norD(2). Similar results were obtained for phosphate absorption, with an increase from 28.2% +/- 5.5% in vehicle-treated rats to 40.2% +/- 4.7% in rats given 10 ng/day 1,25(OH)(2)D(3) and to 32.9% +/- 2.2%, 36.2% +/- 4.5%, and 36.8% +/- 3.8% in rats given 10, 50, and 100 ng/day 19-norD(2), respectively. Vitamin D compounds are believed to increase calcium absorption by inducing a calcium channel (epithelial calcium transporter or calcium transporter-1 [CaT1]) on the luminal membrane, a calcium-binding protein (Calbindin D9k) in the cytosol, and a calcium pump (plasma membrane calcium adenosine triphosphatase-1 [PMCA1]) on the basolateral membrane. Northern-blot analysis of intestinal ribonucleic acid of vitamin D-deficient rats given seven daily injections of vehicle or 100 ng 1,25(OH)(2)D(3) or 19-norD(2) revealed that 19-norD(2) was less potent than 1,25(OH)(2)D(3) in stimulating expression of CaT1, Calbindin D9k and PMCA1. In summary, the reduced calcemic and phosphatemic activities of 19-norD(2) can be attributed to lower potency in stimulating intestinal calcium and phosphate absorption.
Brown
Alex J
AJ
Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA. abrown@imgate.wustl.edu
Finch
Jane
J
Slatopolsky
Eduardo
E
D000818:Animals; D015152:Blotting, Northern; D064026:Calbindins; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000097:blood / Q000493:pharmacokinetics*; D015220:Calcium Channels / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000235:genetics; D002136:Calcium, Dietary / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics; D027682:Cation Transport Proteins; D004872:Ergocalciferols / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics; D010710:Phosphates / Q000493:pharmacokinetics*; D016226:Phosphorus, Dietary / Q000493:pharmacokinetics; D053499:Plasma Membrane Calcium-Transporting ATPases; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D064030:S100 Calcium Binding Protein G / Q000235:genetics; D050916:TRPV Cation Channels
D064026:Calbindins; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D002136:Calcium, Dietary; D027682:Cation Transport Proteins; D004872:Ergocalciferols; D010710:Phosphates; D016226:Phosphorus, Dietary; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C576508:S100g protein, rat; D050916:TRPV Cation Channels; C492241:TRPV5 protein, rat; C084656:paricalcitol; D053499:Plasma Membrane Calcium-Transporting ATPases; C506955:Atp2b1 protein, rat; D000252:Calcium-Transporting ATPases; D002117:Calcitriol; D002118:Calcium