This article provides a good overview of the association of adequate serum 25-hydroxyvitamin D [25(OH)D] levels, reflecting vitamin D intake or production from sun exposure, with reductions in the risks of various cancers [Garland et al., 2006: (http://www.ajph.org/cgi/reprint/96/2/252) (http://www.ncbi.nlm.nih.gov/pubmed/16380576?dopt=Abstract)]. The article discusses the fact that dosages of 2,000 IU/d are likely to not cause toxicity, and a dosage of 4,000 IU/d has been tested for safety in a number of different articles. It would be good for a person to monitor one's serum calcium and talk with his or her doctor before and during supplementation with vitamin D. There are some issues to consider, and the issues don't just have to do with the presence or absence of hypercalcemia [(http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-calcium-channels-and.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html)].
It's good that there's more appreciation of the cell-cycle effects of 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)2D, hormonal vitamin D], but it's astonishing to me that so few of these types of articles mention the molecular biology side, in relation to "cancers" in cell culture experiments or animal models, of vitamin D metabolism. I never hear anyone talking about it, and there's such an overwhelming amount of data and information that's available. It would be one thing if scientists had only found epidemiological evidence, but, as of 2002, about 300 vitamin D analogues [vitamin D receptor (VDR) ligands with reduced calcemic effects (with less potential for causing hypercalcemia), etc.] had been developed to investigate the molecular biology of vitamin D receptor activation in relation to cancers or cellular differentiation, etc. Here's a crude search (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22vitamin+D%22+%22breast+cancer%22+p21) that gives mostly articles relating to molecular biology, to protein-protein interactions that explain the effects of hormonal vitamin D on cellular differentiation and proliferation or apoptosis. One major protein whose expression tends to be upregulated in response to VDR activation (such as by hormonal vitamin D or vitamin D analogues) is p21WAF-1/CIP1 (I'll refer to it as p21, but there are, incidentally, other p21 proteins that aren't regulated strongly by vitamin D, etc.), an inhibitor of more than one cyclin-dependent kinase protein. I forget the details, but p21 can slow cell proliferation and allow for DNA repair, and p21 is, if I remember correctly, one of the proteins whose upregulation allows for the p53-independent effects of vitamin D receptor ligands on the cell cycle. The p53-independent antiproliferative or apoptotic effects of VDR ligands are actually pretty important, and I forget what the reasons are.
Some of those articles, in the search results, discuss the epidemiology alongside the molecular biology, but, to a large extent, the epidemiology-related discussion, in the journals and in the media, especially, ignore the vast amount of indirect evidence, from research in molecular and cellular biology, showing these extremely sophisticated and highly cell-type specific, antiproliferative and differentiating effects of hormonal vitamin D and of vitamin D analogues. The effects of VDR activation are really flexible and depend on the cellular context in which the VDR activation occurs. The same flexibility can occur in the context of the activation of other ligand-activated transcription factors, such as receptors for estrogens or androgens, etc. But my point (and it's just my opinion) is that the epidemiological evidence hasn't just come out of nowhere, and hormonal vitamin D doesn't have some set of "mysterious," unknown, vague effects on different cell types. The presentation of the epidemiological evidence seems to neglect the almost endless, mechanistic data on the regulation of the cell cycle by hormonal vitamin D. That p21 protein is only one of many cell-cycle regulatory proteins that tend to be upregulated, in a kind of differentiation program that varies from cell type to cell type, in response to the activation of the VDR by hormonal vitamin D or by vitamin D analogues. The VDR interacts with large numbers of other transcription factors and proteins and regulates histone acetylation, etc.
Garland et al. (2006) begin their article by describing a Pubmed search on vitamin D levels in relation to cancers, and the authors came up with 13 articles in relation to breast cancer? I understand the desire to only look at certain types of articles, and that's reasonable to a point. But the discrepancy between that number and the thousands of articles that actually exist, relating vitamin D metabolism to mammary epithelial cell differentiation or the like, becomes almost absurd. This very crude search turned up 17,000+ articles that discuss some aspect of "vitamin D" and "breast cancer" and "prevent": (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22vitamin+D%22+%22breast+cancer%22+prevent). By any standard of comparison, that's a pretty big discrepancy between "about 17,500" articles and 13 articles.
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