Improved Cholecalciferol Nutrition in Rats Is Noncalcemic, Suppresses Parathyroid Hormone and Increases Responsiveness to 1,25-Dihydroxycholecalciferol

Abstract

We examined how cholecalciferol (vitamin D) nutrition affected serum 25-hydroxycholecalciferol (25(OH)D) and 1,25-dihydroxycholecalciferol (1,25(OH)₂D). Rats were fed conventional diet (vitamin D, 4.5 iu/g, or 7 nmol/d) or the same diet plus 18 nmol/d of extra vitamin D for 3 wk. The extra vitamin D resulted in greater serum 25(OH)D (51 ± 3, vs. control of 21 ± 2 nmol/L), and kidney mRNA for vitamin D receptor [VDR mRNA] (P = 0.026) and lower serum 1,25(OH)₂D (72 ± 16 vs. control of 161 ± 10 pmol/L, P = 0.001), and parathyroid hormone (PTH) (89 ± 4 vs. control of 160 ± 15 ng/L, P = 0.001). Kidney VDR mRNA relative to GAPDH mRNA correlated inversely with serum 1,25(OH)₂D (r = −0.714, P = 0.006). There were no differences in serum calcium, phosphate, alkaline phosphatase, or weight gain. Experiment 2 compared groups supplemented with 0.2, 2 or 20 nmol/d of vitamin D orally, or 20 nmol/d dermally to see how vitamin D nutrition influenced the response of 1,25(OH)₂D to changes in diet calcium. Vitamin D did not affect urinary calcium or pyridinoline excretion, serum calcium, phosphate, vitamin D binding protein or alkaline phosphatase. In groups given 20 nmol/d of vitamin D, renal mitochondrial 25(OH)D-1α-hydroxylase was lower (P < 0.01) and 25(OH)D-24-hydroxylase was higher (P < 0.05). Higher 25(OH)D concentration was related to proportionally lower 1,25(OH)₂D at every calcium intake, indicating greater tissue sensitivity to 1,25(OH)₂D. We conclude suppression of 1,25(OH)₂D and PTH, and higher renal VDR mRNA and 24-hydroxylase did not involve higher free 1,25(OH)₂D concentration or a first pass effect at the gut. Thus, 25(OH)D or a metabolite other than 1,25(OH)₂D is a physiological, transcriptionally and biochemically active, noncalcemic vitamin D metabolite.