Evidence That 1,25-Dihydroxyvitamin D₃Is the Physiologically Active Metabolite of Vitamin D₃*

THE REALIZATION in the mid-1960s that vitamin D3 is metabolized led to an extensive effort by several laboratories to identify the metabolites produced and determine their biological activities. The identification of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] as the most potent and rapidly acting metabolite of vitamin D3 in stimulating intestinal absorption of calcium and mobilization of bone mineral suggested that this compound is the physiologically active hormonal form of the vitamin. Subsequent studies showing the rapid biological turnover of 1,25-(OH)2D3, the presence of a specific 1,25-(OH)2D3 receptor in target tissues, and the intricate regulation of the renal 25-hydroxyvitamin D3 (25-OHD3)-1-hydroxylase all supported this theory. However, by the late 1970s the possibility that additional metabolites of vitamin D3 have actions distinct from those of 1,25-(OH)2D3, particularly on skeletal mineralization and embryonic chick development, was suggested by several groups. Particular attention has been focused on 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], but other metabolites of vitamin D3, in addition to both 1,25-(OH)2D3 and 24,25-(OH)2D3, potentially have unique physiological functions. This review presents and discusses the evidence that 1,25-(OH)2D3 is the sole physiologically active metabolite of vitamin D3. For detailed information on the metabolism and actions of vitamin D3, the reader is directed to recent reviews on these topics (1–12). No attempt has been made to discuss the data supporting the alternative theory to the one proposed in this review, namely that metabolites of vitamin D3 other than 1,25-(OH)2D3 are required for the complete expression of the actions of vitamin D3. These data have been reviewed elsewhere (13–15). In addition, potential actions of vitamin D3 metabolites on the renal excretion of calcium and phosphorus, the secretion of PTH, and muscular function have not been clarified, and these topics will not be extensively discussed.