Vitamin D Basics

Metabolism

The most common forms of vitamin D are vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). Vitamin D₃ is produced in human skin following exposure to sunlight, whereas vitamin D₂ originates in certain plants and fungi. Both forms of vitamin D are widely available as dietary supplements.

The level of vitamin D is normally stable in human blood. Slight, if any, increase occurs after meals since human diets typically have low vitamin D content, even those containing foods fortified with vitamin D. Exposure of human skin to sunlight usually causes blood vitamin D levels to rise only gradually and modestly.

Both vitamin D₂ and vitamin D₃ are metabolized into pro-hormones by CYP27A, CYP2R1 and certain other cytochrome P450 enzymes located in the liver. These enzymes metabolize vitamin D₂ into the pro-hormone known as 25-hydroxyvitamin D₂ and correspondingly, vitamin D₃ into the pro-hormone known as 25-hydroxyvitamin D₃. The two pro-hormones are collectively referred to as “25-hydroxyvitamin D” or “25(OH)D”. In general, unless an individual is taking vitamin D₂ supplements, most or all of the “25-hydroxyvitamin D” in the human body consists of 25-hydroxyvitamin D₃.

It is widely accepted that the determination of serum 25-hydroxyvitamin D level is the best indicator of an individual’s vitamin D status. The level of vitamin D pro-hormone which is currently considered sufficient is 30 ng/mL, although there is recent evidence that this level should be increased to at least 50 ng/mL for a patient with CKD.

The two vitamin D pro-hormones are further metabolized by the kidneys into hormones by a 1α-hydroxylase enzyme known as CYP27B1, located in the proximal kidney tubule. Vitamin D hormone production in the kidney is tightly regulated by parathyroid hormone (PTH), a hormone secreted by the parathyroid glands. The pro-hormone 25-hydroxyvitamin D₂ is metabolized by CYP27B1 into the hormone known as 1α,25-dihydroxyvitamin D₂ (ercalcitriol). Likewise, 25-hydroxyvitamin D₃ is metabolized by the same enzyme into 1α,25-dihydroxyvitamin D₃ (calcitriol). These hormones, collectively referred to as “1,25-dihydroxyvitamin D”, are secreted by the kidneys into the bloodstream for systemic delivery.

Vitamin D pro-hormones are also metabolized into hormones by organs outside of the kidneys, including skin, lung, parathyroid gland, intestine, those of the immune system (e.g., macrophages) and certain other cells containing CYP27B1 or similar enzymes. Extrarenal production of vitamin D hormones, in contrast to the renal production described above, may not be as precisely regulated. Such extrarenal hormone production provides a “local” supply of hormones that may prove critical to cell growth regulation and the prevention of cancer, autoimmune disorders such as psoriasis and certain types of infection. An adequate “local” production of hormone depends on sufficient levels of circulating 25-hydroxyvitamin D. Epidemiological studies clearly indicate that vitamin D insufficiency, characterized by low serum 25-hydroxyvitamin D levels, associates very strongly with these diseases.