Should I Worried About Tolerable Upper Limits Of Vitamins?

[Travis]

...vitamin a retinol found in butter etc is a pre cursor meaning that it's not 100% that it will convert 100% into the form of vitamin A that is possible to overdose on?

Only a small amount seems to be converted.

Serum levels in 37 fasting healthy volunteers ranged from 2.7 to 4.2 ng/ml, with a mean value of 3.5 ng/ml. These data fitted a normal-Gaussian distribution curve within 95% confidence limits, determined by the Kolmogorov-Smirnov test (25, 26) as shown in Fig. 6.

There is only a small variation in circulating retinoic acid levels. Nanograms per milliliter values are equivalent to parts per million (by mass). Circulating retinoic acid is very tightly controlled:

The well documented biological activity of retinoic acid and the low circulating levels, kept within a narrow range, as clearly demonstrated by our results, suggest a possible hormonal function for this compound.

Possible hormonal function? This study* was done in 1980. Newer ones give similar results but with more accurate techniques. This next one was done in normal subjects:

The subjects (25-58 years old) consisted of 6 men and 20 women in good health, none of whom were being treated with Accutane or taking supplements containing vitamin A or β-carotene. Human blood was obtained by venipuncture in the morning after a 12-h overnight fast.

As you can see, there is a greater range with this extraction method. There is also a slight increase after food intake:

After a meal, the concentration of total RA was 36 % greater compared to fasting subjects. This indicates that the level of RA in human serum is influenced by dietary intake.

The circulating retinol levels are much greater than circulating retinoic acid levels, but they too are narrowly-controlled.

The retinol range is 1.22 to 3.11 μmol/L. This corresponds to 3.49 to 8.91 μg/mL, almost exactly one thousand times the range for retinoic acid. So it seems as though circulating levels of retinoic acid are always about 1000 times smaller than the circulating retinol, which varies little.

The reason for this is that retinol is stored in the liver. The liver pulls-out retinol and links it with fatty acids for storage†

Nearly all of the retinoid present in HSCs is retinyl ester (primarily retinyl palmitate, with smaller amounts of retinyl stearate, retinyl oleate, and retinyl linoleate) (116–119). Normally, unesterified retinol accounts for less than 1% of the total retinoid present within these cells.

But these values do vary widely. Taken from A survey of human liver reserves of retinol in London:

It is generally accepted that the most direct and accurate method of assessing vitamin A status is to measure the concentration of the vitamin in the liver, since it is in this organ that 90% or more of the body’s reserves are located. However (and particularly from the viewpoint of field surveys) the tissue in question is usually inaccessible in living persons because, for ethical reasons, liver biopsies can be performed in only a limited number of clinical situations.

The major feature of the retinol stores was their extraordinary spread, with values ranging from 0 (non-detectable) to 1201 mg/kg. The person with no detectable reserves (incidentally, the only such individual in the entire survey) was a woman aged 86 years who died as a result of cancer, whilst the highest value was obtained from a woman aged 22 years who had committed suicide by taking an acute overdose of barbiturates.

Lower levels are seen in Thailand.

So, I think you should be fine unless you exceed the storage capacity for this vitamin. This seems difficult without consuming liver, fish oil, or supplements. The blood levels should stay in a narrow range unless you take supplements which could perhaps exceed the storage rate of the liver, spilling over into the bloodstream.

The enzyme which converts retinol into retinaldehyde (the direct retinoic acid precursor) is the rate-limiting enzyme, and also has a retinoic acid response element (RARE). This means that this is under control from retinoic acid. This has been unambiguously confirmed‡ experimentally:

In addition, ADH3 [retinol dehydrogenase 3] RAREs contain three TGACC or TGACC-like motifs spaced approximately equally in a 34-bp stretch (Fig. 6c). Our site-directed block mutation of the downstream TGACC sequence of ADH3 located at -289 to -285 bp eliminated the retinoic acid response.

The complimentary sequence of TGACC is ACTGG. When this is flipped around, this becomes GGTCA: the same promoter region seen in the carotene cleavage enzyme mentioned on the previous page. Some researchers talk about one half of the double-helix, and some talk about the other half. They are usually found coiled together inside the cell.

But strangely, a positive-feedback mechanism seems to be at play here:

Since ADH catalyzes one of the steps in retinoic acid synthesis, we hypothesize that this may constitute a positive feedback loop regulating endogenous ADH3 transcription and hence the level of retinoic acid in certain human cells. To achieve homeostasis of retinoic acid levels by using a positive feedback mechanism for stimulating synthesis, it might be necessary to couple this to a mechanism for degrading excess retinoic acid. Indeed, liver and other tissues possess an enzymatic activity, induced by retinoic acid, that oxidizes retinoic acid to the inactive 4-oxo derivative (30). Thus, retinoic acid feedback regulates its degradation as well as its synthesis.

...coupled with a positive-feedback degrading mechanism in the liver, keeping the levels in range.

He believes that some retinol is taken-up by each cell and converted to retinoic acid directly for use:

According to this model, retinoic acid potentially functions as an intracrine hormone to self-regulate intracellular retinoic acid levels by controlling ADH (retinol dehydrogenase) gene expression. Intracrine regulation is defined as a mechanism whereby hormones are synthesized and act within a cell without the need for exit and reentry, as is the case for hormones that act by endocrine, paracrine, or autocrine mechanisms (27). Retinoic acid has also been proposed to function in a paracrine fashion, affecting cells closely neighboring the cells that synthesize the hormone.

With the positive-feedback conversion within the cell, you might assume that small variations in retinol could produce large changes in retinoic acid. But on second thought, the enzyme would only be able to convert the retinol already inside of the cell. So you probably shouldn't expect much amplification at this stage, if any.

And considering the measured values, we know there isn't much variation in retinol. The only way I can see pathological changes is through high-dose supplements, liver, or alcohol. Ethanol actually competes with the same enzyme that converts retinol into retinaldehyde:

If class I ADH does play a role as a retinol dehydrogenase during human embryonic development, one can devise a molecular mechanism that helps explain the pathogenesis of fetal alcohol syndrome (10). Ethanol acts as a teratogen, causing abnormalities in nervous system and limb morphogenesis in those suffering from fetal alcohol syndrome (4, 37). Ethanol is a known substrate for all human class I ADH isozymes with Km values of approximately 1 to 2 mM (26, 43), and it acts as a competitive inhibitor of human liver class I ADH retinol oxidation with a Ki of 0.36 mM (26). It is reasonable to propose that the teratogenic effects of ethanol on nervous system and limb morphogenesis may be mediated by a competitive substrate inhibition of the retinoloxidizing activity of fetal ADH, which would be expected to reduce the synthesis of retinoic acid known to play a critical role in morphogenesis of these tissues (12, 40, 41). Such an inhibition may reduce the concentration of retinoic acid to a level that is insufficient to correctly specify spatial patterns in target tissues of the developing embryo.

He has written an entire article on this subject as well, but I haven't read that one. It sounds interesting. Low retinoic acid levels appear to be just as damaging as high ones during development.

It seems so nicely controlled that I wouldn't worry much about it unless you drink alot of alcohol, take Accutane, or eat liver in considerable amounts. Diets high in refined foods could lead to a deficiency, but that too would also be hard to accomplish.


‡Duester, G., et al. "Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis." Molecular and Cellular Biology 11.3 (1991): 1638-1646.
†O'Byrne, Sheila M., and William S. Blaner. "Retinol and retinyl esters: Biochemistry and physiology Thematic Review Series: Fat-soluble vitamins: vitamin A." Journal of lipid research 54.7 (2013): 1731-1743.
Huque, T. "A survey of human liver reserves of retinol in London." British Journal of Nutrition 47.2 (1982): 165-172.
Ballew, Carol, et al. "Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988–1994." The American journal of clinical nutrition 73.3 (2001): 586-593.
*Tang, G. W., and Robert M. Russell. "13-cis-retinoic acid is an endogenous compound in human serum." Journal of lipid research 31.2 (1990): 175-182.

 

[Steve123]

Only a small amount seems to be converted.

There is only a small variation in circulating retinoic acid levels. Nanograms per milliliter values are equivalent to parts per million (by mass). Circulating retinoic acid is very tightly controlled:
View attachment 6419

Possible hormonal function? This study* was done in 1980. Newer ones give similar results but with more accurate techniques. This next one was done in normal subjects:

View attachment 6420
As you can see, there is a greater range with this extraction method. There is also a slight increase after food intake:

The circulating retinol levels are much greater than circulating retinoic acid levels, but they too are narrowly-controlled.
View attachment 6424
The retinol range is 1.22 to 3.11 μmol/L. This corresponds to 3.49 to 8.91 μg/mL, almost exactly one thousand times the range for retinoic acid. So it seems as though circulating levels of retinoic acid are always about 1000 times smaller than the circulating retinol, which varies little.

The reason for this is that retinol is stored in the liver. The liver pulls-out retinol and links it with fatty acids for storage†

But these values do vary widely. Taken from A survey of human liver reserves of retinol in London:


View attachment 6423
Lower levels are seen in Thailand.

So, I think you should be fine unless you exceed the storage capacity for this vitamin. This seems difficult without consuming liver, fish oil, or supplements. The blood levels should stay in a narrow range unless you take supplements which could perhaps exceed the storage rate of the liver, spilling over into the bloodstream.

The enzyme which converts retinol into retinaldehyde (the direct retinoic acid precursor) is the rate-limiting enzyme, and also has a retinoic acid response element (RARE). This means that this is under control from retinoic acid. This has been unambiguously confirmed‡ experimentally:
The complimentary sequence of TGACC is ACTGG. When this is flipped around, this becomes GGTCA: the same promoter region seen in the carotene cleavage enzyme mentioned on the previous page. Some researchers talk about one half of the double-helix, and some talk about the other half. They are usually found coiled together inside the cell.

But strangely, a positive-feedback mechanism seems to be at play here:

...coupled with a positive-feedback degrading mechanism in the liver, keeping the levels in range.

He believes that some retinol is taken-up by each cell and converted to retinoic acid directly for use:

With the positive-feedback conversion within the cell, you might assume that small variations in retinol could produce large changes in retinoic acid. But on second thought, the enzyme would only be able to convert the retinol already inside of the cell. So you probably shouldn't expect much amplification at this stage, if any.

And considering the measured values, we know there isn't much variation in retinol. The only way I can see pathological changes is through high-dose supplements, liver, or alcohol. Ethanol actually competes with the same enzyme that converts retinol into retinaldehyde:

He has written an entire article on this subject as well, but I haven't read that one. It sounds interesting. Low retinoic acid levels appear to be just as damaging as high ones during development.

It seems so nicely controlled that I wouldn't worry much about it unless you drink alot of alcohol, take Accutane, or eat liver in considerable amounts. Diets high in refined foods could lead to a deficiency, but that too would also be hard to accomplish.


‡Duester, G., et al. "Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis." Molecular and Cellular Biology 11.3 (1991): 1638-1646.
†O'Byrne, Sheila M., and William S. Blaner. "Retinol and retinyl esters: Biochemistry and physiology Thematic Review Series: Fat-soluble vitamins: vitamin A." Journal of lipid research 54.7 (2013): 1731-1743.
Huque, T. "A survey of human liver reserves of retinol in London." British Journal of Nutrition 47.2 (1982): 165-172.
Ballew, Carol, et al. "Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988–1994." The American journal of clinical nutrition 73.3 (2001): 586-593.
*Tang, G. W., and Robert M. Russell. "13-cis-retinoic acid is an endogenous compound in human serum." Journal of lipid research 31.2 (1990): 175-182.

Thought i replied to this post Travis.. Thanks so much for this... Could i ask though.. When we find info on vitamin a contents of certain foods on cronometer or what ever is out there.. Are they most of the type roughly accurate and safe to go by? For example if i was to go by Vitamin A contents of foods from sources on the internet then these are them below.. (If you was to do a search for the vitamin A of these items you'd likely find lower amounts of vit A in these foods but i just picked sources that say the vit a is higher to be on safe side....
-Whole milk 2 litre = 3400IU Vit A .. Even lower for 2% and Skimmed milk.
- Cheese 100g = 1100IU Vit A
- Butter 100g = 3500IU Vit A
- Eggs Two = 700-1000IU Vit A

..Would you go by these amounts? Or do you have a more reputable safer source to go by? Would this amount on a daily basis be safe to consume and pose no risk for a vitamin A overdose if i consumed this amount for a longish period of time if i ever did?

 

[Travis]

Sign-up for free at cronometer.com. You have to use your e-mail address to do it, but it's very easy. You just enter what you eat and it does all of the standard calculations.

What you eat wouldn't be acutely toxic, but it might put you into positive retinol liver storage mode. The levels can actually change gradually over years. Human liver contents vary greatly, even in young people. They vary by about 1,000 fold yet blood concentrations always stay within a very narrow range.

The cronometer is kinda fun. You can even turn it into a game in which you try to get 100% of everything without using pills.

 

[Steve123]

Sign-up for free at cronometer.com. You have to use your e-mail address to do it, but it's very easy. You just enter what you eat and it does all of the standard calculations.

What you eat wouldn't be acutely toxic, but it might put you into positive retinol liver storage mode. The levels can actually change gradually over years. Human liver contents vary greatly, even in young people. They vary by about 1,000 fold yet blood concentrations always stay within a very narrow range.

The cronometer is kinda fun. You can even turn it into a game in which you try to get 100% of everything without using pills.

Just got it now.. do you think cronometer is safe and accurate enough to go by when trying to work out vit A of things, I've compared it with some other vitamin calculator sources and it comes quite similar..

As long as I'm getting under the Tolerable upper limit for Vit A Retinol of 10,000IU on a daily basis, wouldn't I be safe long term as that TUL is the apparent highest amount people have consumed without adverse affects? (Although I've heard apparently it used to be like 25,000IU etc.. And 10,000IU is very low.. )

Thanks again though Travis!

 

[Steve123]

Just got it now.. do you think cronometer is safe and accurate enough to go by when trying to work out vit A of things, I've compared it with some other vitamin calculator sources and it comes quite similar..

As long as I'm getting under the Tolerable upper limit for Vit A Retinol of 10,000IU on a daily basis, wouldn't I be safe long term as that TUL is the apparent highest amount people have consumed without adverse affects? (Although I've heard apparently it used to be like 25,000IU etc.. And 10,000IU is very low.. )

Thanks again though Travis!

Just realised how stupid of a question that was.. it should never be an issue at all for the amount I consume, I probably would never go past 8,000IU of Vit A daily..I also don't consume liver or any really high sources of vit a retinol ever.. just the daily dairy fat.. sorry for pestering with this type of stuff !

 

[Travis]

The one group that had problems, the Scandinavians, drank vitamin A-fortified milk in the '90s. I think this was government-mandated at the time. They also had consumed fish oil, and fish-liver oil.

These are two supplemental items over what most Americans and Europeans consume. This is why they had problems. The anti-dairy websites never mention this when implicating milk for causing osteoporosis. It's not the "unabsorbable calcium" or some other nebulous woo factor, it's the increased retinol causing increased bone-turnover in the (relative) absence of vitamin D.

Only vitamin A-fortified milk above the 50th parallel only seems to do this to any great extent. Fish-liver oil should probably be avoided, both for the polyunsaturated acids and for the excessive retinol.

I used to think that the difference between consuming retinol and β-carotene was an issue, even for people just eating natural foods. But I don't think it's something to be overly concerned with either way unless you have liver problems. But in that case, the high trytophan levels in the blood would probably make you forget* all about vitamin A.

*Literally: Knell, A. J., et al. "Dopamine and serotonin metabolism in hepatic encephalopathy." Br Med J 1.5907 (1974): 549-551.