Guest guest Posted December 30, 2008 Report Share Posted December 30, 2008 > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > I would be be interested in any thoughts about it Hi athan; There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process. First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene expression regulated by the active metabolite (1,25- dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses. Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D. Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25- hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium) tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25- hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25- hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know. While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/hormone deficient, and avoid taking too much of any one nutrient/vitamin/hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you also need either DHA of vitamin A? It's not just one hormone/vitamin/nutrient that matters, but rather it's best to have a good balance for everything to work properly! I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards, Dave (father of (23); PSC 07/03; UC 08/03) P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail. Quote Link to comment Share on other sites More sharing options...
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