Calcifediol is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-α position (lower right of the molecule) to form calcitriol (1,25-dihydroxycholecalciferol, 1,25(OH)2D). The conversion of calcifediol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene. The activity of CYP27B1 is increased by parathyroid hormone, and also by low calcium or phosphate. Following the final converting step in the kidney, calcitriol is released into the circulation. By binding to vitamin D-binding protein, calcitriol is transported throughout the body, including to the intestine, kidneys, and bones. Calcitriol is the most potent natural ligand of the vitamin D receptor, which mediates most of the physiological actions of vitamin D. In addition to the kidneys, calcitriol is also synthesized by certain other cells, including monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, modulating body defenses against microbial invaders by stimulating the innate immune system.