Regulation of 1 and 24 hydroxylation of vitamin D metabolites in the proximal tubule.

Calcium and phosphate are critical for numerous physiological processes. Consequently, the plasma concentration of these ions are tightly regulated. Calcitriol, the active form of vitamin D, is a positive modulator of mineralization as well as calcium and phosphate metabolism. The molecular and physiological effects of calcitriol are well documented. Calcitriol increases blood calcium and phosphate levels by increasing absorption from the intestine, and resorption of bone. Calcitriol synthesis is a multistep process. A precursor is first made via skin exposure to UV, it is then 25-hydroxylated in the liver to form 25-hydroxyitamin D. The next hydroxylation step occurs in the renal proximal tubule via the 1-αhydroxylase enzyme (encoded by ) thereby generating 1,25-dihydroxyvitamin D, that is, calcitriol. At the same site, the 25-hydroxyvitamin D 24-hydroxlase enzyme encoded by can hydroxylate 25-hydroxyvitamin D or calcitriol to deactivate the hormone. Plasma calcitriol levels are primarily determined by the regulated expression of and . This occurs in response to parathyroid hormone (increases ), calcitriol itself (decreases and increases ), calcitonin (increases or decreases and increases ), FGF23 (decreases and increases ) and potentially plasma calcium and phosphate levels themselves (mixed effects). Herein, we review the regulation of and transcription in response to the action of classic phophocalciotropic hormones and explore the possibility of direct regulation by plasma calcium.