it is best to read the full article in the links above because it is very interesting, here is abstract conclusions
Circulating vitamin D, the parent compound, likely plays an important physiological role with respect to the vitamin D endocrine/autocrine system, as a substrate in many tissues, not originally thought to be important. Based on emerging data from the laboratory, clinical trials, and data on circulating 25-hydroxyvitamin D amassed during many decades, it is likely that for the optimal functioning of these systems, significant vitamin D should be available on a daily basis to ensure stable circulating concentrations, implying that variation in vitamin D dosing schedules could have profound effects on the outcomes of clinical trials because of the short circulating half-life of intact vitamin D.
Extraordinary advances in vitamin D research have occurred since Adolf Windaus was awarded the Nobel Prize for its discovery in 1928 (1). Over the next several decades vitamin D was studied mostly in dietary terms and later in metabolic studies, culminating in the discovery of 25-hydroxyvitamin D [25(OH)D] by the Deluca lab in 1968 (2). Intense study of 25(OH)D over the next 2 years resulted in the discovery of the hormonal form of vitamin D—1,25-dihydroxyvitamin D [1,25(OH)2D]—by various research groups (3–6). At that point, research into any potential biological function/contribution of circulating intact vitamin D basically ceased because 1,25(OH)2D became the major focus, followed by a later change in focus in the mid to late 1980s when circulating 25(OH)D was deemed the best nutritional status indicator for vitamin D and was shown to be associated with secondary hyperparathyroidism and cancer incidence in a way that circulating 1,25(OH)2D was not (7, 8). Thus, outcome relationships with circulating 25(OH)D have been an intense focus of research while the potential role of the parent compound intact vitamin D in the circulation has not been studied in the same way, especially because measuring this compound in the circulation has been very difficult until recently.
There is no debate that to become fully active, vitamin D must be metabolized to 1,25(OH)2D; however, what has not been fully appreciated in this metabolic scheme is the importance of cellular accessibility of the parent compound vitamin D, as well as that of 25(OH)D. The current literature shows clearly that vitamin D is vastly more accessible than 25(OH)D for internalization into any given cell type with the exception of cells expressing the megalin-cubilin system (9), the kidney and parathyroid gland, that provide the vitamin D endocrine system. In contrast, most other cell types depend on their paracrine/autocrine environment, but the availability of circulating 25(OH)D to these cells is reduced because it is tightly bound to the vitamin D binding protein (VDBP). Intact vitamin D is bound to VDBP much less strongly (10–12), with ample evidence in the literature to support this concept, showing that only the “free” metabolite can enter the cell easily for activation (13, 14). This fact becomes very important when designing clinical studies for vitamin D in the selection of dosing regime, ie, whether to give supplements at daily, weekly, monthly, or longer intervals, because such different regimes could well explain much of the discordance in outcomes that has been observed in interventional studies on infection and cancer (15–27). These data might prove more consistent with consideration of the provision of intact vitamin D as a major substrate for local activation of vitamin D in target tissues, in addition to the availability of circulating 25(OH)D. A further problem is that it is not yet known how much vitamin D is required and what is the dosing frequency to ensure a stable circulating concentration of intact vitamin D that is adequate for optimal tissue function.
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