Vitamin D Basics

Metabolism

Blood levels of vitamin D are normally present at stable concentrations in human blood. Slight, if any, increases occur after meals since human diets typically have low vitamin D content, even those containing foods fortified with vitamin D. Exposure to sunlight causes blood vitamin D levels to rise only gradually and modestly.

The most widely recognized forms of vitamin D are vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). While both forms occur naturally, and are widely available as food supplements, vitamin D₃ is produced photobiochemically in the skin following exposure to sunlight, whereas vitamin D₂ originates in certain plants and fungi.

Both vitamin D₂ and vitamin D₃ are metabolized into pro-hormones by CYP27A 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”. In general, unless an individual is receiving vitamin D₂ supplements, most or all of the “25-hydroxyvitamin D” consists of 25-hydroxyvitamin D₃.

It is widely accepted that determination of serum pro-hormone 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 growing evidence suggesting that this level should be increased to at least 40 ng/mL.

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. Activation of the vitamin D pro-hormones occurs under tight regulation by parathyroid hormone (PTH), a hormone secreted by the parathyroid glands. The pro-hormone 25-hydroxyvitamin D₂ is metabolized by CYP27B1 into the active hormone known as 1α,25-dihydroxyvitamin D₂ (or ercalcitriol). Likewise, 25-hydroxyvitamin D₃ is metabolized by the same enzyme into the hormone 1α,25-dihydroxyvitamin D₃ (or calcitriol). These two vitamin D hormones, which are secreted by the kidneys into the blood for systemic delivery, are collectively referred to as “1,25-dihydroxyvitamin D”.

Vitamin D pro-hormones are also metabolized into hormones by organs outside of the kidneys, including skin, lung, 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, is not precisely regulated.  Such extrarenal hormone production contributes little to the circulating blood levels of 1,25-dihydroxyvitamin D, but 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 often 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.