25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand.
25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-28-2009 05:42 PM


Expert Low-Carber


25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand.25-Hydroxyvitamin D(3) 1alpha-hydroxylase encoded by CYP27B1 converts 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3), a vitamin D receptor ligand.

25-Hydroxyvitamin D(3) has been regarded as a prohormone.

Using Cyp27b1 knockout cells and a 1alpha-hydroxylase-specific inhibitor we provide in four cellular systems, primary mouse kidney, skin, prostate cells and human MCF-7 breast cancer cells, evidence that 25-hydroxyvitamin D(3) has direct gene regulatory properties.

The high expression of megalin, involved in 25-hydroxyvitamin D(3) internalisation, in Cyp27b1(-/-) cells explains their higher sensitivity to 25-hydroxyvitamin D(3).

25-Hydroxyvitamin D(3) action depends on the vitamin D receptor signalling supported by the unresponsiveness of the vitamin D receptor knockout cells.

Molecular dynamics simulations show the identical binding mode for both 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) with the larger volume of the ligand-binding pocket for 25-hydroxyvitamin D(3).

Furthermore, we demonstrate direct anti-proliferative effects of 25-hydroxyvitamin D(3) in human LNCaP prostate cancer cells.

The synergistic effect of 25-hydroxyvitamin D(3) with 1alpha,25-dihydroxyvitamin D(3) in Cyp27b1(-/-) cells further demonstrates the agonistic action of 25-hydroxyvitamin D(3) and suggests that a synergism between 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) might be physiologically important.

In conclusion, 25-hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand with gene regulatory and anti-proliferative properties.


When I first read this paper in full I thought WOW. This will not only upset the Marshall Protocol lobby but also excite the Vitamin D community. I don't understand why it has been greeted with such total silence.

Surely the fact that we now know that raising 25(OH)D to the level it works as a hormone gives us the chance to directly control our ability to regulate the proliferation of cancer cells.

They may have shown that at 40ng/ml 100nmol/l no anti cancer proliferation is measurable but further work may well show that at the level human breast milk flows replete with D3 60ng/ml there is a sufficiently greater concentration to over time slow cancer progression. It surely lends support to the idea that levels around 80ng/ml 200nmol/l would be better a slowing cancer growth.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 05:39 AM


Expert Low-Carber


I put this through Babel Fish but it still didn't come out in English.


No Longer in Texas, but can't change my name

I was on the side of righteousness, and like any fundamentalist, I could only stay there by avoiding information. - Lierre Keith
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 07:29 AM


Expert Low-Carber


Wouldn't it be nice if researchers put a plain english version of the paper's findings.

Up till now the understanding was that Vitamin D3 required two hydroxylations (one in the liver and the next in the kidneys) before it became the active hormone Calcitriol.

The in between stage Calcidiol is the form that circulates in the blood and it was regarded as a prohormone.

These guys have shown that both on slides and through computer modelling that Calcidiol, that we previously thought was inert, is in fact capable of binding with the Vitamin D receptor to make it function, and it also works in collaboration with Calcitriol (the really potent stuff from the kidneys) so rather than just having to rely on Calcitriol we can, if we have sufficiently high levels of circulating 25(OH)D3 have an operational vitamin D system without the need to higher amounts of calitriol.

The crucial point is that they tested out calidiol (25(OH)D3) on breast and cancer cells, on slides, at various concentrations and at 40ng/ml ~ 100nmol/l but couldn't measure anti proliferative activity, at higher concentrations they did.

There is currently a disagreement between Vitamin D researchers as to whether a level around 40ng/ml or higher 60ng/ml is best to recommend as the minimum level for the general public.

For Caucasians maximum bone mineral density can be certain at levels above 42ng/ml while to allow human breast milk to flow replete with D3 and guarantee that babies are born with a sufficient Vitamin D status to guarantee they can absorb maximum amounts of calcium and have good BMD 6400iu/daily is required and a 25(OH)D level above 58.8ng/ml

As it is clear calcidiol is required in quantity to operate as a hormone it adds weight to the idea that the higher primitive level (60ng/ml) at which human breast milk flows replete with D3, is probably safer in the long run as there is no measurable anti cancer proliferation potential at the lower level.

For UK readers this should be an alarm call to raise vitamin D3 status. Our current average adult level in winter is below 20ng/ml less than half that required for BMD and less than a third of that required for optimum levels of vitamin D3 in breast milk.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 04:17 PM


Expert Low-Carber


Thanks for the translation. I'm surprised, also that there has not been more publicity about this.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 04:34 PM


Expert Low-Carber


Since accurate vitamin D dosage varies greatly from one individual to the next, I am surprised that the "powers that be" are not pushing individual testing to conclude the proper amount of D3 on an individual basis instead of a minnimum daily allowance. I mean isn't the minnimum allowance pretty much useless?
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 05:08 PM


Unregistered

 

There's no free web access to the entire article so I have to rely on Ted's summary and the abstract on this, but this paper was about what looks to be in vitro (test tube/petri dish) experiments, in this case, cultures of human cells. Such studies are a first step in a long process, and in this day and age we rarely hear much in the general media about such relatively preliminary investigations. Part of that might be media bias and whatnot, but part of that is also because the point of such publications is more to validate one's efforts so far (usually to secure future funding or justify funding to date), and not so much to garner publicity or herald major medical breakthroughs. It is not all that uncommon for in vitro results to be considerably different from that which is eventually observed in live whole organisms (in vivo). The cells of "immortal cell lines" used in such human cell cultures differ from normal or even tumor cells in the intact organism.

I further suspect this to be the case based on part of the abstract quoted in the OP:

Quote:The synergistic effect of 25-hydroxyvitamin D(3) with 1alpha,25-dihydroxyvitamin D(3) in Cyp27b1(-/-) cells further demonstrates the agonistic action of 25-hydroxyvitamin D(3) suggests that a synergism between 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) might be physiologically important.

The wording of the scientists here is crucial.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 07:00 PM


Expert Low-Carber


Indeed but as we know for certain that 10,000iu/daily is absolutely safe.
It is pretty much common sense that outdoor living naked humans evolved with the potential for vitamin D replete human breast milk and if we know the level at which human breast milk flows replete with Vitamin D3 those with an inclination for a safe bet may think it possible that the natural level that allows babies to be born vitamin D sufficient and with access to vitamin D sufficient breast milk may also be around the level at which sufficient calicidiol concentrations are available for the hormonal action of calcidiol to be measurable. As this is around the level associated with Least incidence of chronic illness there may be a reason for that association?

It is not only safe but also sensible to avoid the potential consequences of Developmental vitamin D de?ciency causes abnormal brain development by ensuring the natural level of vitamin D3 that ensures adequate Vitamin D supplementation during lactation to support infant and mother.

No one is suggesting anything other than recognizing the fact that at higher concentrations Calcidiol is active in it's own right as a hormone.

Providing one stays within the daily intake that is equivalent to the daily sun exposure our DNA evolved to function best with, and acquire a status equivalent to the primitive level at which babies are born vitamin D replete and with access to vitamin D3 replete breast milk I find it hard that anyone could have any valid objections to such an idea. This is the level Dr Davis finds his heart disease patients achieve greatest reduction in risk factors.

Were any peer reviewed published research papers done before the introduction of glass windows or the popularization of picture windows and conservatories?

Our early ancestors didn't have the opportunities we now have for basking in Vitamin D3 depleting UVB deficient, UVA replete sunlight.

Nor did they have the chance to consume HFCS that induces vitamin D insufficiency.
If we didn't examine the consequences of high fructose impact on vitamin D status prior to the introduction of HCFS we certainly don't need to have peer reviewed research before rectifying the consequences of those unscientific actions.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 07:06 PM


Expert Low-Carber


I agree that the evidence I've read is convincing enough for me to supplement vitamin D3 in myself and my kids (DH refuses, oh, well). Guess I'll quit procrastinating and get that test from the Vitamin D Council and check my levels, too.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 12-29-2009 07:13 PM


Unregistered

 
It is pretty much common sense that outdoor living naked humans evolved with the potential for vitamin D replete human breast milk and if we know the level at which human breast milk flows replete with Vitamin D3 those with an inclination for a safe bet may think it possible that the natural level that allows babies to be born vitamin D sufficient and with access to vitamin D sufficient breast milk may also be around the level at which sufficient calicidiol concentrations are available for the hormonal action of calcidiol to be measurable. As this is around the level associated with Least incidence of chronic illness there may be a reason for that association? ...
No doubt! Not questioning the research or it's potential implications. I take a lot of D myself. My post was addressing the lack of attention to this study and the reasons I felt as to why.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-26-2010 01:11 AM


Expert Low-Carber


Indeed but as we know for certain that 10,000iu/daily is absolutely safe.
It is pretty much common sense that outdoor living naked humans evolved with the potential for vitamin D replete human breast milk and if we know the level at which human breast milk flows replete with Vitamin D3 those with an inclination for a safe bet may think it possible that the natural level that allows babies to be born vitamin D sufficient and with access to vitamin D sufficient breast milk may also be around the level at which sufficient calicidiol concentrations are available for the hormonal action of calcidiol to be measurable. As this is around the level associated with Least incidence of chronic illness there may be a reason for that association?

It is not only safe but also sensible to avoid the potential consequences of Developmental vitamin D de?ciency causes abnormal brain development by ensuring the natural level of vitamin D3 that ensures adequate Vitamin D supplementation during lactation to support infant and mother.

No one is suggesting anything other than recognizing the fact that at higher concentrations Calcidiol is active in it's own right as a hormone.

Providing one stays within the daily intake that is equivalent to the daily sun exposure our DNA evolved to function best with, and acquire a status equivalent to the primitive level at which babies are born vitamin D replete and with access to vitamin D3 replete breast milk I find it hard that anyone could have any valid objections to such an idea. This is the level Dr Davis finds his heart disease patients achieve greatest reduction in risk factors.

Were any peer reviewed published research papers done before the introduction of glass windows or the popularization of picture windows and conservatories?

Our early ancestors didn't have the opportunities we now have for basking in Vitamin D3 depleting UVB deficient, UVA replete sunlight.

Nor did they have the chance to consume HFCS that induces vitamin D insufficiency.
If we didn't examine the consequences of high fructose impact on vitamin D status prior to the introduction of HCFS we certainly don't need to have peer reviewed research before rectifying the consequences of those unscientific actions.
Ted, do you know of any studies that have looked at the relationship between Vitamin D and Vitamin A? Some of the literature I've read says that A is antagonistic to D, but others say both should be taken in a balanced manner. If the latter is true, then my next question is at what ratio should they be taken together? Just wondering if you've run across this, I can't seem to find a definitive answer.

Ellen
http://www.healthy-eating-politics.com
http://www.ketogenic-diet-resource.com
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-26-2010 08:10 AM


Expert Low-Carber


I don't think there is a definitive answer to this question.
On one side we have Garland and Cannell saying that only small amounts of vitamin a are worth taking because Vitamin A can attach to Vitamin D receptors, and on the other Masterjohn suggests more Vitamin A is required. (however from natural not synthetic sources)

I take a double strength cod liver oil that has 2500 IU but I also take 5000iu/d vitamin D3 and get regular UVB exposure. Some people say take them apart but when you think about it cod liver oil was traditionally used as a good source of vitamin d3 (before some started standardizing the vitamin A content with synthetic rather than natural vit A)
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-26-2010 10:14 PM


Expert Low-Carber


Not to highjack this post, but I have had two patients have negative reaction to taking D3. One at small amounts (2,000 iu), the other was taking quite a bit to load her system.

Any ideas what might cause that?

Mackay Rippey

Has your weight loss stalled because your body clock is out of sync?
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-26-2010 11:01 PM


Moderator


Mackay,
What did they experience? I had severe muscle stiffness (Couldn't move my neck), sleeplessness, and some anxiety (about not sleeping well) for several weeks. It eventually went away, but I had no idea why and never occurred to me till later that it might have been the vitamin D3. (The symptoms started around the time I started taking it.) Turns out, it was most likely magnesium deficiency which was aggrivated by taking higher doses of D3. Anyways, I'm fine now. Just curious what you've seen.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-27-2010 01:21 AM


Expert Low-Carber


One had severe muscle pain similar to what you experienced and she took modest amounts of D3.

The other client I cannot remember right now. I'll have to ask.

Mackay Rippey

Has your weight loss stalled because your body clock is out of sync?
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-27-2010 07:54 AM


Expert Low-Carber


I'm not sure aggravated is the right word to describe the way raising your 25(OH)D to above 42ng/ml allows your body to absorb the maximum amount of calcium from diet/supplements.
Calcium requires magnesium to counterbalance it's actions.
Calcium tenses muscles
Calcium excites neurones
Magnesium relaxes muscle fibers and calms neurones.
68% of US adults don't take in the current RDA for magnesium let alone get sufficient vitamin D3. Modern fast growing varieties of vegetables and grains don't have the same magnesium content as before so that adds to the problem. Urban pollution and upper atmospheric air pollution block UVB reaching the ground so even if people in town do get 20minutes sunshine at midday there is no guarantee they get much vitamin D3.
Idealy use both magnesium and Vitamin D3.
The vitamin D3 1000iu for each 25lbs you currently weight once daily.
Magnesium 2.5 to 4.5 mg per pound of ideal body weight daily.

Reason for the difference in current weight for D3 and ideal weight for mag is that vitamin D is fat soluble and gets locked up in fat cells when insulin levels are high. Therefore people who are overweight tend to use and need more D3 than people ideal weight.
The magnesium is not fat soluble so it isn't so critical. Magnesium is best taken in smaller amount THROUGH the day with each meal and also, if you have trouble sleeping, 30~60mins before going to bed.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-27-2010 08:14 AM


Expert Low-Carber


The muscle pain you describe in you later post sounds like magnesium deficiency was being revealed. Krispin has some good magnesium information You can't really overdose on the magnesium because as soon as you take too much the surplus ends up in the colon and because it is hygroscopic it attracts water and the result is loose stools. So at this point back down the magnesium intake to the point that stools are as soft/firm as required.

Quote:One at small amounts (2,000 iu),
If you look at the banner here you see 2000iu brings most people to just above the point they maximize calcium uptake (32ng) and are best able to fix it in bones (42ng)


Quote:the other was taking quite a bit to load her system.
But that isn't untypical. Moving up to 6000iu/daily gets most people above that 40ng/ml lowest acceptable threshold. Though there is such variability that even at higher levels their is the odd person who doesn't respond
Quote:Any ideas what might cause that?
I'd suggest inflammation in the gut. People with crohn's and celiac, gluten intolerance invariably have low vitamin D3 for this reason. I have suggested to people in this position to snip the gelatin capsule of a brand such as this
Country Life, Vitamin D3, 5,000 IU, 200 Softgels
that comes in MCT oil and massage the vitamin 3 in MCT directly into the skin.
MCT is easily absorbed and easily metabolised and as vitamin D is naturally made near the skin surface doing this MAY be an effective route for raising status in cases where orally doesn't seem to be solving the problem. As Vitamin D3 is degraded by light choose a skin that isn't subject to UV exposure.

MCT is less likely to go rancid than fish/soy/olive oil and therefore would not leave a smell.

It would be helpful if anyone who has used this massage technique for raising vitamin D status let readers know if it's successful. I can't see any logical reason why it wouldn't work. People who use Vitamin D cremes for treating skin conditions raise their 25(OH)D status. It could be useful for kids where you want to avoid those dreadful kids vitamins full of nasty sweeteners.

By coincidence I went from here to here Where I find someone reporting back after following information provided online
Quote:I was taking 50,000 a week, and it took 6 weeks and my levels were up to 55ng (137.5nmol/l) from 30ng (75nmol/l) , so I am taking it every 2 weeks, and will check again in a few months.

I also have found that since I added 600mg of magnesium I no longer get cramps in my hips or legs or toes.. and I sleep like a lamb
I take Calcium also, 450 one in my multi and a single 250 at bedtime.


I take the 50,000 in the am,,,seems to be fine for me...
It's nice when people report back as others can read the follow up and learn from that experience although we have to remember that we are all different in many ways. 50,000iu every fortnight =3571iu/daily. But the poster lives in Alpine Calif so should be getting UVB from sunshine to support the supplemental intake.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-27-2010 12:35 PM


Moderator


I'm not sure aggravated is the right word to describe the way raising your 25(OH)D to above 42ng/ml allows your body to absorb the maximum amount of calcium from diet/supplements.
Calcium requires magnesium to counterbalance it's actions.
Calcium tenses muscles
Calcium excites neurones
Magnesium relaxes muscle fibers and calms neurones.
68% of US adults don't take in the current RDA for magnesium let alone get sufficient vitamin D3. Modern fast growing varieties of vegetables and grains don't have the same magnesium content as before so that adds to the problem. Urban pollution and upper atmospheric air pollution block UVB reaching the ground so even if people in town do get 20minutes sunshine at midday there is no guarantee they get much vitamin D3.
Idealy use both magnesium and Vitamin D3.
The vitamin D3 1000iu for each 25lbs you currently weight once daily.
Magnesium 2.5 to 4.5 mg per pound of ideal body weight daily.

Reason for the difference in current weight for D3 and ideal weight for mag is that vitamin D is fat soluble and gets locked up in fat cells when insulin levels are high. Therefore people who are overweight tend to use and need more D3 than people ideal weight.
The magnesium is not fat soluble so it isn't so critical. Magnesium is best taken in smaller amount THROUGH the day with each meal and also, if you have trouble sleeping, 30~60mins before going to bed.
Thanks Ted,
This is great information. I'm taking almost exactly the amount of Vit D you recommended. Based on what you've said about D getting trapped in the fat cells, would a person losing weight have a slightly lower requirement?

As far as magnesium is concerned, I have 200 mg supplements. I usually take 1 in the morning and one at night. Based on an ideal weight of 200 pounds, I guess i need to take one more. To be frank, the only reason I haven't been taking 3 a day already is because I'm afraid I'll have bathroom issues. Any suggestions?
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-27-2010 04:30 PM


Expert Low-Carber


Let your body decide how much extra you require.
Magnesium chloride (Dead Sea Salts) or Magnesium Sulphate (Epsom Salts) are both pretty cheap if you buy a 25kg sack. In the UK we have Country Stores, Equine supplies and similar chains selling to smallholders, small farmers, horsey country folks needs. They use magnesium chloride in the drinking water to calm tense horses. But you can throw some in your bathwater you don't have to have a horse in the bath with you. If you've arthritic aches and pains then the Epsom salts (a bit more expensive) would be better because both the magnesium and the sulphate would be helping (people used to go to spas for treatment in sulphate rich baths)
Either way a 20minute hot soak in magnesium rich bathwater allows your skin to absorb what you need without it upsetting the digestive system. You can also get a magnesium oil which is a supersaturate solution of magnesium chloride. Very expensive for what it is. If you leave your sack of magnesium chloride open you will have a supersaturated solution of magnesium chloride all over the garage floor so be warned reseal the bag or better still transfer it to a bin with a good air tight lid.

If you want to try making a small amount of magnesium chloride oil just leave a kg of magnesium chloride in a large jug in the bathroom or other steamy place and in a few days it will have attracted sufficient water to dissolve itself in and you can rub this on your skin and you'll take up the magnesium transdermaly.
It's not really an oil but it feels a bit oily as it's slippery.
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-27-2010 10:26 PM


Moderator


Great suggestions. Thanks. I shower more than I bathe. How often would one need to do the magnesium bath?
RE: 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. , 01-28-2010 12:58 AM


Expert Low-Carber


Thanks Ted, we were thinking a magnesium deficiency also, but the addition of magnesium did not seem to help.

I may try again starting with the magnesium and then adding the D3.

I have taken 50,000 iu at a time and have experienced no ill effects.

I do, however, tend to eat food we have grown ourselves,

Mackay Rippey

Has your weight loss stalled because your body clock is out of sync?