Dietary Phosphate Deprivation Increases Renal Synthesis and Decreases Renal Catabolism of 1,25-Dihydroxycholecalciferol in Guinea Pigs

Abstract

In guinea pigs, dietary phosphate deprivation decreases plasma phosphate concentration, increases plasma 1.25-dihydroxycholecalciferol [1,25-(OH)2D3] concentration and causes hypercalcemia concurrent with the maximal increase in plasma 1,25-(OH)2D3 levels. Our objective was to determine whether increased synthesis or decreased catabolism contributed to the elevation in plasma 1,25-(OH)2D3. Preliminary experiments using renal mitochondria from guinea pigs fed a control diet revealed that 23,25-dihydroxycholecalciferol [23,25-(OH)2D3], not 24,25-dihydroxycholecalciferol [24,25-(OH)2D3], was the reciprocal side-chain metabolite to 1,25-(OH)2D3 in this species. An assay employing guinea pig renal mitochondria was used to measure the renal synthesis of 1,25-(OH)2D3 and 23,25-(OH)2D3 from [3H]25-OH-D3. These metabolites were unequivocally identified by combinations of HPLC, ultraviolet spectrophotometry and mass spectrometry. This renal mitochondrial assay was subsequently used to investigate the effect of dietary phosphate deprivation on guinea pig vitamin D metabolism. Within 1 wk the rate of synthesis of 1,25-(OH)2D3 was maximal in phosphate-deprived guinea pigs. This rate was significantly (P less than 0.005) higher than that achieved in same-day control guinea pigs. Conversely, within 1 d the synthesis of 23,25-(OH)2D3 was significantly (P less than 0.005) decreased in phosphate-deprived guinea pigs. Similarly, the rate of 1,25-(OH)2D3 metabolism was decreased within 1 d of dietary phosphate deprivation and was at a minimum within 1 wk. This rate was significantly (P less than 0.005) less than that attained in same-day control guinea pigs. These results suggest that both increased synthesis and decreased metabolism of 1,25-(OH)2D3 contribute to the plasma 1,25-(OH)2D3 elevation that occurs in response to dietary phosphate deprivation.