Determinants of circulating 1,25-dihydroxyvitamin D(3) levels: the role of renal synthesis and catabolism of vitamin D

Special Issue: Proceedings of the 12th Workshop on Vitamin D, Maastricht, The Netherlands, 6-10 July 2003. Edited by R. Bouillon, A.W. Norman and J.R. PasqualiniDetails of the molecular mechanisms determining levels of the secosteroid, 1,25-dihydroxyvitamin D₃ (1,25D) remain to be elucidated. The current paradigm for the control of serum 1,25D levels is the tight regulation of renal 25-hydroxyvitamin D-1α-hydroxlase (CYP27B1) activity by a number of physiological factors. 1,25D production is also regulated by the cytochrome P450 enzyme, 25-hydroxyvitamin D-24-hydroxylase (CYP24), which through side chain hydroxylation reactions, inactivates 1,25D. We have recently demonstrated that renal CYP27B1 and CYP24 expression contribute equally to regulating serum 1,25D levels. We now describe the contribution of renal Vitamin D receptor (VDR) expression in determining serum 1,25D levels. Serum 1,25D levels were decreased when the dietary calcium intake was increased. We measured mRNA levels for CYP27B1, CYP24 and VDR receptor in kidney RNA extracts from animals fed diets containing different levels of calcium, ranging from 0.05 to 1%. Serum 1,25D levels were negatively correlated with renal CYP24 mRNA levels (R²=0.35, P<0.01) while renal VDR is positively correlated with renal CYP24 mRNA (R²=0.80, P<0.001). However, only renal VDR mRNA remained a significant determinant of renal CYP24 expression when both these variables were included in multiple linear regression analysis (multiple R²=0.89, P