How Does Vitamin D Get Converted to Calcitriol? A Detailed Look

January 9, 2026 •

2 min read

According to the National Institutes of Health, vitamin D is not a true vitamin, but rather a prohormone that must be converted to its active form before the body can use it. This vital transformation, detailing how vitamin D gets converted to calcitriol, is an essential metabolic process that ensures proper calcium regulation and bone health.

Quick Summary

The conversion of inactive vitamin D into its active hormonal form, calcitriol, occurs through a two-step hydroxylation process in the liver and kidneys, respectively.

Key Points

Two-Step Process: The conversion of vitamin D to calcitriol involves two key hydroxylation steps occurring sequentially in the liver and kidneys.
Liver's Role: The liver performs the first hydroxylation, converting vitamin D (cholecalciferol) into calcidiol (25-hydroxyvitamin D) via the CYP2R1 enzyme.
Kidney's Role: The kidneys carry out the second hydroxylation, transforming calcidiol into the active hormone, calcitriol (1,25-dihydroxyvitamin D), using the CYP27B1 enzyme.
Hormonal Regulation: The final conversion step in the kidneys is tightly regulated by hormones like parathyroid hormone (PTH) and phosphate levels to maintain calcium balance.
Clinical Significance: Impairment in liver or kidney function can disrupt this metabolic pathway, leading to vitamin D deficiency symptoms despite adequate intake.
Active Form: Calcitriol is the fully activated form of vitamin D, binding to cellular receptors to perform its biological functions throughout the body.

The Initial Step: 25-Hydroxylation in the Liver

Before it can be utilized, ingested vitamin D or that produced in the skin must first be processed by the liver. This is the first critical step in the activation pathway. Once in the bloodstream, vitamin D (cholecalciferol, or D3) is transported to the liver, where it undergoes its first hydroxylation reaction.

The Role of the CYP2R1 Enzyme

The enzyme primarily responsible for this initial conversion is 25-hydroxylase, mainly cytochrome P450 2R1 (CYP2R1).
This enzyme adds a hydroxyl group ($OH$) at the 25th carbon position of the vitamin D molecule.
This reaction forms 25-hydroxyvitamin D, also known as calcidiol or calcifediol.

Calcidiol is the main circulating form of vitamin D, typically measured to assess vitamin D status. It is then released into the bloodstream, bound to a vitamin D-binding protein (DBP), and transported to the kidneys for the final activation step.

The Final Step: 1α-Hydroxylation in the Kidneys

The second and final hydroxylation step is tightly regulated and produces the active hormone. This process mainly occurs in the kidneys but can also happen in other tissues.

The Role of the CYP27B1 Enzyme

In the kidneys, calcidiol encounters the enzyme 1α-hydroxylase, or CYP27B1.
This enzyme adds a second hydroxyl group at the 1-alpha position of the calcidiol molecule.
This final reaction creates the biologically active form of vitamin D, called 1,25-dihydroxyvitamin D, or calcitriol.

Calcitriol production in the kidneys is highly controlled by factors like low blood calcium and high parathyroid hormone (PTH), which stimulate 1α-hydroxylase activity. High phosphate levels and fibroblast growth factor 23 (FGF23) inhibit it.

Comparison of Key Vitamin D Metabolites


Metabolite	Chemical Name	Production Site	Function	Circulating Half-Life
Vitamin D (D3)	Cholecalciferol	Skin, Diet	Prohormone (inactive)	~2 months
Calcidiol	25-hydroxyvitamin D	Liver	Storage form (largely inactive)	~15 days
Calcitriol	1,25-dihydroxyvitamin D	Kidneys, other tissues	Active Hormone	~hours

Conclusion: The Importance of the Activation Cascade

The two-step enzymatic process transforming inactive vitamin D into active calcitriol is vital for human physiology. This pathway ensures effective regulation of calcium and phosphate, crucial for bone mineralization, muscle function, and nerve transmission. Issues in this process due to liver or kidney disease can cause health problems like rickets and osteomalacia. For those with impaired metabolism, calcitriol supplementation may be necessary to bypass this conversion.

To learn more about the specific enzymes involved and genetic conditions affecting this pathway, you can visit the MedlinePlus CYP2R1 gene page.

Frequently Asked Questions

The primary function of calcitriol, the active form of vitamin D, is to increase blood calcium levels by promoting the absorption of calcium and phosphate from the intestines and regulating bone resorption.

Vitamin D is considered an inactive prohormone because it lacks the necessary hydroxyl groups to bind effectively to the vitamin D receptor (VDR) in cells. It requires enzymatic activation in the liver and kidneys to become the potent hormone calcitriol.

The enzyme 25-hydroxylase, primarily coded by the CYP2R1 gene, is responsible for the first activation step, adding a hydroxyl group to vitamin D to form calcidiol.

In individuals with kidney disease, the final conversion step of calcidiol to calcitriol by the enzyme 1α-hydroxylase can be impaired. This can lead to low levels of active calcitriol and related bone disease.

Calcitriol production is tightly controlled by several factors. High levels of parathyroid hormone (PTH) stimulate the final conversion step, while high blood phosphate and FGF23 levels inhibit it.

Calcidiol (25-hydroxyvitamin D) is the main circulating, storage form of vitamin D, created in the liver. Calcitriol (1,25-dihydroxyvitamin D) is the biologically active, hormonal form, produced primarily in the kidneys.

Yes, while the kidneys are the primary site, other tissues such as the placenta and activated macrophages can also produce small amounts of calcitriol.