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

Journal

EXPERIMENTAL BIOLOGY AND MEDICINE
Volume 247, Issue 13, Pages 1103-1111

Publisher

SAGE PUBLICATIONS LTD
DOI: 10.1177/15353702221091982

Keywords

Vitamin D; calcium; kidney; PTH; CaSR; calcitriol

Funding

  1. Women and Children's Health Research Institute - Stollery Children's Hospital Foundation
  2. Canadian Institutes of Health Research
  3. National Sciences and Engineering Research Council

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Calcium and phosphate play crucial roles in physiological processes, while calcitriol acts as a positive regulator of mineralization and calcium and phosphate metabolism. The synthesis of calcitriol involves a multi-step process, primarily regulated by CYP27B1 and CYP24A1, with expression influenced by various hormones.
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-alpha hydroxylase enzyme (encoded by CYP27B1) thereby generating 1,25-dihydroxyvitamin D, that is, calcitriol. At the same site, the 25-hydroxyvitamin D 24-hydroxlase enzyme encoded by CYP24A1 can hydroxylate 25-hydroxyvitamin D or calcitriol to deactivate the hormone. Plasma calcitriol levels are primarily determined by the regulated expression of CYP27B1 and CYP24A1. This occurs in response to parathyroid hormone (increases CYP27B1), calcitriol itself (decreases CYP27B1 and increases CYP24A1), calcitonin (increases or decreases CYP24A1 and increases CYP27B1), FGF23 (decreases CYP27B1 and increases CYP24A1) and potentially plasma calcium and phosphate levels themselves (mixed effects). Herein, we review the regulation of CYP27B1 and CYP24A1 transcription in response to the action of classic phophocalciotropic hormones and explore the possibility of direct regulation by plasma calcium.

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