What is the mechanism of Calcitriol?

Calcitriol, also known as 1,25-dihydroxyvitamin D3, is the active form of vitamin D in the body. It plays a critical role in maintaining calcium and phosphate balance, which are vital for healthy bone formation, muscle function, and overall cellular processes. Understanding the mechanism of calcitriol involves exploring its synthesis, regulation, and physiological effects.

Calcitriol synthesis begins with the conversion of cholesterol to 7-dehydrocholesterol in the skin. Upon exposure to ultraviolet B (UVB) radiation from sunlight, 7-dehydrocholesterol is converted to previtamin D3, which subsequently isomerizes to form vitamin D3 (cholecalciferol). Vitamin D3 can also be obtained from dietary sources like fatty fish, fortified dairy products, and supplements.

Once in the body, vitamin D3 undergoes two hydroxylation reactions to become calcitriol. The first hydroxylation occurs in the liver, where vitamin D3 is converted to 25-hydroxyvitamin D3 (calcifediol) by the enzyme 25-hydroxylase. Calcifediol is then transported to the kidneys, where the enzyme 1α-hydroxylase hydroxylates it at the 1-alpha position, producing calcitriol.

Calcitriol exerts its effects by binding to the vitamin D receptor (VDR), a nuclear receptor found in various tissues throughout the body, including the intestines, bones, kidneys, and parathyroid glands. Upon binding to calcitriol, the VDR undergoes a conformational change that allows it to heterodimerize with the retinoid X receptor (RXR). This VDR-RXR complex then binds to specific DNA sequences known as vitamin D response elements (VDREs) located in the promoter region of target genes.

The binding of the VDR-RXR complex to VDREs initiates the transcription of genes involved in calcium and phosphate homeostasis. In the intestines, calcitriol upregulates the expression of calcium-binding proteins and calcium channels, enhancing the absorption of dietary calcium and phosphate. In the kidneys, calcitriol promotes the reabsorption of calcium in the renal tubules, reducing urinary calcium loss. Additionally, calcitriol stimulates the release of calcium and phosphate from the bones into the bloodstream by activating osteoclasts, the cells responsible for bone resorption.

Calcitriol also plays a role in regulating parathyroid hormone (PTH) levels. PTH is a hormone secreted by the parathyroid glands in response to low blood calcium levels. It acts to increase blood calcium by stimulating the release of calcium from bones, increasing renal calcium reabsorption, and promoting the formation of calcitriol. Calcitriol, in turn, provides negative feedback to the parathyroid glands, inhibiting PTH secretion and thus preventing excessive calcium release and bone resorption.

Beyond calcium and phosphate homeostasis, calcitriol has additional roles in the body. It modulates immune function by influencing the activity of various immune cells, including macrophages, dendritic cells, and T cells. Calcitriol enhances the innate immune response while modulating the adaptive immune response to prevent excessive inflammation. It also has antiproliferative and prodifferentiation effects on various cell types, which may have implications in cancer prevention and treatment.

In summary, calcitriol is the active form of vitamin D that plays a crucial role in maintaining calcium and phosphate balance through its actions on the intestines, kidneys, bones, and parathyroid glands. It achieves these effects by binding to the vitamin D receptor, regulating gene transcription, and interacting with other hormones like PTH. Beyond its classic roles, calcitriol influences immune function and cellular differentiation, highlighting its importance in overall health and disease prevention.