Abstract
Because humans evolved at equatorial latitudes, without modern clothing and shelter, their vitamin D supply would have been equivalent to at least 100 w g day -1 (4000 units day -1 ). Thus, the human genome was selected for under conditions where the circulating 25-hydroxyvitamin D (25(OH)D) concentration was greater than 100 nmol l -1 . This contrasts with modern humans in whom serum 25(OH)D is typically half that. This review poses the question of whether our genome was optimized for higher levels of vitamin D nutrition than are prevalent today. Many tissues possess 25(OH)D-1-hydroxylase and they can produce 1,25-dihydroxyvitamin D (1,25(OH)2D) for local, paracrine use. Furthermore, the activity of existing 1-hydroxylase depends upon the 25(OH)D concentration in a manner different from the substrate relationships for other hormone-producing systems. The functional, in vivo Km for 1,25(OH)2D production is higher than the concentration of substrate, 25(OH)D. That is, a doubling in 25(OH)D concentration will double the capacity for 1,25(OH)2D production in vivo . This applies not only to the kidney, but also to every tissue that possesses 1-hydroxylase. So far, there is little direct evidence for the health implications of this unique substrate relationship. The amounts of vitamin D that have been used in randomized clinical studies were small and do show some effect. Vitamin D supplementation with 20 w g day -1 (800 IU day -1 ) is now recognized as preventing bone loss, reducing fracture risk, lowering blood pressure, and lowering circulating parathyroid hormone concentrations. However, the benefits of a higher vitamin D supply are implicated by the circumstantial evidence of epidemiological studies that reflect differences in the sun exposure that produces vitamin D in skin. These potential benefits of greater vitamin D nutrition include a reduction in the occurrence of breast, prostate, and bowel cancers and the autoimmune conditions of multiple sclerosis and insulin-dependent diabetes. Randomized clinical trials into these conditions should focus on the higher, physiological doses of nutritional vitamin D whose consumption has recently been shown to be safe for adults. Unfortunately, the term 'vitamin D' is so commonly misapplied to analogs of its hormonal form that research and side-effects relating to those analogs can be misinterpreted as being somehow related to nutrition.