Friday, August 26, 2011

VITAMIN D: how a vitamin becomes a true hormone.

    

 

Calcium intake is well know to represent a very important factor affecting bone mass, bone biomechanical alteration and consequntly bone fracture incidence. Low calcium intake in particular with consequent decrease in intestinal calcium absorption is the gatekeeper in bone disease induction. It has been demonstrated from basic studies on osteoporotic patients that low intestinal calcium absorption is striclty related to loss or decrease activity of steroid hormonal compounds such as estrogens and activated form of Vitamin D3 (1,25 dihydrixyVitamin D3) at epithelial intestinal level. With aging in particular there is a decline in calcium absorption efficiency, related to intestinal loss of Vitamin D3 receptors or resistance/lower actictivity of these receptors to the action of 1,25 dihydroxyVitamin D3. Also seasonal variations in sunlight exposure profundly affect the level of Vitamin D3 synthetized in our skin by irradiation with ultraviolet wave length of our skin tissue. Pre Vitamin D2 and Pre Vitamin D3 better called ergocalciferol and colecalciferol, introduced with the diet respectively from vegetable and from animals foods, are efectively transformed on skin tissue in true Vitamin D2 and Vitamin D3 by automaintained non enzymatic reaction due only to exposure of our skin tissue to sunlight ultraviolet irradiation.

CYP27A1 hydroxylase

After sunlight activation Vitamin D3 is transported into our body linked to protein carriers on the first time to the liver, where it is hydroxylated by a cytocrome P450 dependent enzyme called 25 hydroxylase CYP27A1. At this level a first selection is performed by hydroxylating electively the choleclaciferol derivatives (i.e. Vitamin D3) more than ergocalciferol derivatives (i.e. Vitamin D2). From this first evidence is not effective the therapeutical administration of vegetable form of vitamin D, leading on the contrary to adecrease in levels of active hydroxylated forms of Vitamin D3. Measurement of plasma levels of 25-hydroxy Vitamin D3 is universally considered the main index of individual body reserve of Vitamin D3. However, many controversies exist, and recently published Guidelines outlined this topic, about optimal plasmatic levels achievable in human in order to prevent Vitamin D3 deficiency. Accordingly, a seasonal fluctuation in hormonal vitamin D3 are present in humans related to sunlight exposure with greater levels reached during spring and summer seasons, and lower levels during fall and winter seasons. Again, interindividual variations between individuals are present according to proportion of time spent in indoor and outdoor activities. Moreover, also variations according to latitute degree of countries where people live are present if we consider that sunlight irradiation is most importantat near tropical area of the world compared to northern countries.

CYP27B1 hydroxylase

After liver activation 25 hydroxyVitamin D3 is transported to the kidney proxymal convoluted tubules in order to be fully activated by 1-alfa hydroxylase enzyme cytocrome P450 CYP27B1. This hydroxylative enzyme has been profoundly studied thanks to the more evident regulation by hormonal axis devoted to calcium-phosphate homeostasis. However, as we can see later, 1 alfa hydroxylase activity is not so relevant to know the individual needs of Vitamin D3 supplementation with fortified foods. On the contrary, it is important for the synthesis of active hormonal Vitamin D3 hydroxylated in 25 and 1 alfa carbons allowing a global interaction with zinc fingher sites of intranuclear Vitamin D receptors present in target tissues. In particular , it has been largely demonstrated both in vitro and in vivo that 1 alfa hydroxylase is sensitive to stimulating action of parathyroid hormone, estrogens and probably androgenic steroids hormones, Growth Hormone/Insulin growth factor 1.

CYP24A1 hydroxylase

Responsible for catabolism of Vitamin D3 into liver secreted “ calcitroic acid “ 24 hydroxylase enzyme CYP24A1 has been only recently subjected to an accurated studies. In particular the genetic demonstrations of genetic polymorphisms leading to inactive mutated forms of CYP24A1 hydroxylase has been recently confirmed also in clinical background as responsible of Vitamin D3 toxicity. In particular the Idiopathic Infantile Hypercalcemia ( milder form ) also called Lightwood type (OMIM 143880) has been demonstrated in 3 affected patients linked to mutations in CYP24A1 gene expression. It is possible that clinically noted interindividual variations in Vitamin D3 need by fortified foods in humans could be due to inactivating mutations in CYP24A1 gene. Interestingly a new hormonal axis has been invoved into regulation of CYP24A1 expression: called FGF23/KLOTHO axis. Klotho is a protein with glycosidase activity able to modify the FGF Receptor present at kidney level for FGF23. FGF23 as bee demonstrated to be a potent stimulator of CYP24A1 and a potent inhibitor of CYP27B1 suggesting in this way a more complex picture compared to the past, involving two homeostatic system for phospho-calcium metabolism:

      PTH/ Vitamin D3 axis: CYP27B1

      FGF23/ KLOTHO axis: CYP27B1 and CYP24A1

References

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Chang Q, Hoefs S, van der Kemp AW et al. The beta glucosidase Klotho hydrolyzes and activates the TRPV5 Channel. Science 2005;310:490-3.

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Priè D, Huart V, Bakouh N et al. Nephrolithiasis and osteoporosis associated with hypophosohatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 2002;347:983-91.

Johnsson KB, Zahradnik R, Larsson T et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X linked hypophosphatemia. N Engl J Med 2003;348:1656-63.

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Schlingmann KP, Kaufmann M, Weber S et al. Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia. N Engl J Med 2011;365:410-21.

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