title: Reduced hepatic synthesis of calcidiol in uremia.
abstract: Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D(3) C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P < 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D(3) or 1alpha-hydroxyvitamin D(3), respectively, suggesting impaired C-25-hydroxylation of vitamin D(3). Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms.
authors.affiliation: Service de Néphrologie et Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Michaud
authors.forename: Judith
authors.initials: J
authors.lastname: Naud
authors.forename: Denis
authors.initials: D
authors.lastname: Ouimet
authors.forename: Christian
authors.initials: C
authors.lastname: Demers
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Petit
authors.forename: Francois A
authors.initials: FA
authors.lastname: Leblond
authors.forename: Alain
authors.initials: A
authors.lastname: Bonnardeaux
authors.forename: Marielle
authors.initials: M
authors.lastname: Gascon-Barré
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
mesh_terms: D000818:Animals; D002112:Calcifediol / Q000096:biosynthesis*; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism*; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology; D016105:Parathyroidectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000378:metabolism*
chemical_list: D010281:Parathyroid Hormone; D002762:Cholecalciferol; D053493:Cholestanetriol 26-Monooxygenase; D002112:Calcifediol