Comparative effects of doxercalciferol (1α-hydroxyvitamin D₂) versus calcitriol (1α,25-dihydroxyvitamin D₃) on the expression of transporters and enzymes in the rat in vivo.
Effects of 1.28 nmol/kg doxercalciferol [1α(OH)D₂], a synthetic vitamin D₂ analog that undergoes metabolic activation to 1α,25-dihydroxyvitamin D₂, the naturally occurring, biologically active form of vitamin D₂, on rat transporters and enzymes were compared with those of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃, active form of vitamin D₃; 4.8 and 6.4 nmol/kg] given on alternate days intraperitoneally for 8 days. Changes were mostly confined to the intestine and kidney where the vitamin D receptor (VDR) was highly expressed: increased intestinal Cyp24 and Cyp3a1 messenger RNA (mRNA) and a modest elevation of apical sodium-dependent bile salt transporter (Asbt) and P-glycoprotein (P-gp) protein; increased renal VDR, Cyp24, Cyp3a9, Mdr1a, and Asbt mRNA, as well as Asbt and P-gp protein expression; and decreased renal PepT1 and Oat1 mRNA expression. In comparison, 1α(OH)D₂ treatment exerted a greater effect than 1,25(OH)₂D₃ on Cyp3a and Cyp24 mRNA. However, the farnesoid X receptor -related repressive effects on liver Cyp7a1 were absent because intestinal Asbt, FGF15 and portal bile acid concentrations were unchanged. Rats on the alternate day regimen showed milder changes and lessened signs of hypercalcemia and weight loss compared with rats receiving daily injections (similar or greater amounts of 0.64-2.56 nmol/kg daily ×4) described in previous reports, showing that the protracted pretreatment regimen was associated with milder inductive and lesser toxic effects in vivo.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Edwin C Y
EC
Chow
Myrte
M
Sondervan
Cheng
C
Jin
Geny M M
GM
Groothuis
K Sandy
KS
Pang
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004872:Ergocalciferols / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D010758:Phosphorus / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014815:Vitamins / Q000494:pharmacology*
D001647:Bile Acids and Salts; D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014815:Vitamins; D010758:Phosphorus; C042533:1 alpha-hydroxyergocalciferol; D003577:Cytochrome P-450 Enzyme System; D002117:Calcitriol; D002118:Calcium