24-Hydroxylase: potential key regulator in hypervitaminosis D 3 in growing dogs

A group of growing dogs supplemented with cholecalciferol (vitamin D3; HVitD) was studied vs. a control group (CVitD; 54,000 vs. 470 IU vitamin D3/kg diet, respectively) from 3 to 21 wk of age. There were no differences in plasma levels of Pi and growth-regulating hormones between groups and no signs of vitamin D3 intoxication in HVitD. For the duration of the study in HVitD vs. CVitD, plasma 25-hydroxycholecalciferol levels increased 30- to 75-fold; plasma 24,25-dihydroxycholecalciferol levels increased 12- to 16-fold and were accompanied by increased renal 24-hydroxylase gene expression, indicating increased renal 24-hydroxylase activity. Although the synthesis of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] was increased in HVitD vs. CVitD (demonstrated by [3H]1,25(OH)2D3 and increased renal 1alpha-hydroxylase gene expression), plasma 1,25(OH)2D3 levels decreased by 40% as a result of the even more increased metabolic clearance of 1,25(OH)2D3 (demonstrated by [3H]1,25(OH)2D3 and increased gene expression of intestinal and renal 24-hydroxylase). A shift of the Ca set point for parathyroid hormone to the left indicated increased sensitivity of the chief cells. Effective counterbalance was provided by hypoparathyroidism, hypercalcitoninism, and the key regulator 24-hydroxylase, preventing the development of vitamin D3 toxicosis.