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Three versions of vitamin D can activate the vitamin D receptor in some cells

Posted on: October 24, 2013   by  [email protected]


It doesn’t pay to be overconfident. There is so much we don’t understand. Our latest humility lesson comes from Finland. Researchers there have discovered that in some cells at least, 1a,25-dihydroxy-vitamin D [1a,25(OH)2D, which is sometimes written as 1,25(OH)2D] is not the only form of vitamin D that can activate the nuclear vitamin D receptor.

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12 Responses to Three versions of vitamin D can activate the vitamin D receptor in some cells

  1. Rita and Misty

    Hey Tom–I enjoyed your article very much.

    Taken from your article: “The next big surprise is that the version of vitamin D that regulates the second-most number of genes (171) is 25(OH)D.”

    I’m certainly not a physician nor am I a research scientist, SO I apologize upfront if my thought process is inappropriate here….but in plain words: 25(OH)D is the prohormone produced in the liver after the liver breaks down vitamin D3…correct?

    Think (just think) of the total disease burden to be lessened if folks maintained an optimal 25(OH)D level….

    But, what is an optimal 25(OH)D level?

    Is it hubris (really) to think that we require a level similar to our hunter/gatherer ancestors?

    By the way, the graphics on this article are superb…and remind me of the passage…”it is easier for a camel to go through the eye of a needle than for a rich man to enter the kingdom of God….”

    Yet, (and this is ironic), the universal monetary cost savings to society would be tremendous if the vitamin D deficiency pandemic were ended. And, dollars are required to better this physical world. Money is fundamentally a necessary tool to provide care to and for humanity. Little gets accomplished on good faith only…Certainly not the (expensive) research required to learn and understand about science…and this includes vitamin D research.

    There is the Golden Rule: Those who have more are required to do more. In my opinion, how can our future generations forgive us for less?

  2. Tom Weishaar

    Rita – in the past I’ve referred to 25(OH)D as the “storage” form of vitamin D – it’s the form that’s measured in a vitamin D blood test, obviously. I’m not sure what to call it now, since in terms of the vitamin D receptor it appears to be as active as 1,25(OH)2D, which I’ve referred to in the past as the “activated” form. These findings may force us to come up with a new vocabulary.

  3. Rita and Misty

    I think we are living in an amazing time regarding vitamin D… I only hope that funding for necessary research will be available to help us answer those very important questions!

    I also look forward to the 25(OH)D test being made standard on the blood panel…and I look forward to food fortification.

    And of course, we need to work on sunshine regaining its appropriate place in all our lives….

    Burning and sun sensitivity to me are signs of vitamin D deficiency.

  4. Ian

    24R,25 (OH)2D has been in the limelight before, not just as a breakdown product but as an active metabolite:

    In this editorial:

    and some articles:
    Chemopreventive effects of 24R,25-dihydroxyvitaminD3 on glandular stomach carcinogenesis induced in rats by N-methyl-N’-nitro-N-nitrosoguanidine and sodium chloride.
    Shinichiro Ikezaki, Akiyoshi Nishikawa, Fumio Furukawa, et al.
    Cancer Res 1996;56:2767-2770.

    24R,25-dihydroxyvitamin D3: an essential vitamin D3 metabolite for both normal bone integrity and healing of tibial fracture in chicks.
    Seo EG, Einhorn TA, Norman AW
    Endocrinology. 1997 Sep;138(9):3864-72.

    and from the same authors:

    Studies on 24R,25-dihydroxyvitamin D3: evidence for a nonnuclear membrane receptor in the chick tibial fracture-healing callus.
    Kato A, Seo EG, Einhorn TA, Bishop JE, Norman AW.
    Bone. 1998 Aug;23(2):141-6.


    The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease.
    Bosworth CR, Levin G, Robinson-Cohen C, Hoofnagle AN, Ruzinski J, Young B, Schwartz SM, Himmelfarb J, Kestenbaum B, de Boer IH.
    Kidney Int. 2012 Sep;82(6):693-700. doi: 10.1038/ki.2012.193. Epub 2012 May 30.

  5. Tom Weishaar

    Ian – thanks for all the links. This makes it clear why the researchers included 24,25-D in their study.

  6. Tom Weishaar

    I forgot to mention that in this study the three forms of vitamin D were all the D3 (animal) forms. It would be interesting to find out if the D2 (plant) forms activate the same genes, as well as whether substances that seem to mimic some of the metabolic effects of vitamin D, such as curcumin (found in turmeric), activate anything,

  7. Rita and Misty

    Inflammation is the culprit of modern day disease(s)…in my opinion we need to look back to Africa…to our ancestral origins…for healthy inspiration:

    * appropriate sun exposure for optimal 25(OH)D level
    * paleo/primal eating habits to improve gut health
    * adequate exercise and sleep
    * establishment of social networks

    These all play a role in our good health.

  8. Ian

    Tom I would also like to see some information on the D2 analogue in the catabolism to 24,25(OH)2D. I suspect the kinetics of the conversion are different. Kinetics do play an important part in function and availability, I suspect particularly in epigenetic function, something many researchers forget to study or include in analyses.

    So far much of the comparison of D2 and D3 have been in the comparative levels of 25(OH)D and while equivocal I think more recent studies are saying that D3 supplementation leads to higher 25(OH)D levels.

    Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis.
    Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S.
    Am J Clin Nutr. 2012 Jun;95(6):1357-64. doi: 10.3945/ajcn.111.031070. Epub 2012 May 2.

    Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months.
    Logan VF, Gray AR, Peddie MC, Harper MJ, Houghton LA.
    Br J Nutr. 2013 Mar 28;109(6):1082-8. doi: 10.1017/S0007114512002851. Epub 2012 Jul 11.

  9. John Cannell, MD

    I wonder if native cholecalciferol generates any kind of steroid signal?

  10. Rita and Misty

    I’m going to apologize upfront (because I’m not a scientist), but I think it might be relatively easy to test if cholecalciferol generates any kind of steroid signal. You could use a modified mouse cell that didn’t allow for conversion to 25(OH)D or 1,25(OH)2D. Right?

  11. [email protected]

    Very interesting article. I’m not a scientist either, but I wonder if it’s a valid assumption that CYP24A1 begins “the breakdown process” of the other forms of vit D. How do we know that in prostate tissue, at least, where an anti-cancer function is certainly valuable, 24R,25(OH)2D isn’t the PREFERRED form of vit D. I suppose that a lack of negative feedback could possibly suggest otherwise, but that may not be necessary with an active metabolic pathway. And what is known about competition between these three forms? I don’t recall hearing about any.

    It seems that vit D is looking more and more like the “estrogen” triad model.
    “The more we learn, the more we realize we don’t know.”

  12. Ian

    Here is another recent study on the difference between D2 and D3:

    Calculated free and bioavailable vitamin D metabolite concentrations in vitamin D-deficient hip fracture patients after supplementation with cholecalciferol and ergocalciferol.
    Glendenning P, Chew GT, Inderjeeth CA, Taranto M, Fraser W.D.

    Bone. 2013 Oct;56(2):271-5

    We now need a lot of work to identify the roles of the different metabolites including cholecalciferol. As Dr. Cannell says, “is there any steroid activity from cholecalciferol itself”?.

    I have always thought that it is massive assumption that the only active metabolite was 1,25(OH)2D.

    Good studies on bone, cardiovascular, neurological and immune systems should systematically examine the activity of all four metabolites.

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