Low Toxin Diet Grant Genereux's Theory Of Vitamin A Toxicity

[Amazoniac]

Came across this again:

- Excretion of Vitamin A Metabolites in the Bile

"In contrast to retinoyl-notDiokine-glucuronide, which promotes the growth of vitamin A-deficient rats[1] and reverses the cornification of vaginal epithelial cells induced by vitamin A deficiency,[11] retinotaurine has very little or no biological activity. Most probably, it represents merely an excretory form of retinoic acid.[12] It is not known, however, if amidases present in the bacterial flora of the small intestine can hydrolyze the amide linkages in retinotaurine, allowing possible resorption and reutilization of the liberated retinoid in an enterohepatic circulation."​

For convenience and a different perspective:

- Nutrition, Aging, and the Elderly (978-1-4899-2537-4)

Spoiler

--
- Synthesis of coenzyme A ester of retinoic acid: Intermediate in vitamin A metabolism
- Activation of retinoic acid by coenzyme A for the formation of ethylretinoate
- Incorporation of retinoic acid into proteins via retinoyl-CoA
- Formation of Retinoylated Proteins from Retinoyl-CoA in Rat Tissues

 

[Troubles]

I just got banned from Grant Genereux forum because I asked question that destroys his theory. I think Grant knows that his theory is hoax, but he wants to get people really sick and gets some kind of pleasure from it.

So this was the question that got me instantly banned. I have had super oily skin since I was 14 years old and nothing else has reduced my oily skin except isotretinoin, even with super low dose 10 mg twice a week. I have megadosed retinyl palmitate and beta carotene, but those two won't reduce my oily skin, not even a little. So Grant says that all vitamin a sources, beta carotene and retinyl palmitate eventually gets converted inside body to basically isotretinoin. If this is true then why my oily skin gets reduce by 100% with isotretinoin only?

 

[tim333]

One of the symptoms of Hypervitaminosis A is oily skin. One tends to get dandruff and cracked lips so skin can be flaky but it tends to overstimulate the sebaceous glands as well. In Hypervitaminosis A retinol is present at higher than normal levels in the bloodstream along with ATRA, 13-cis-retinoic acid and other molecules that are created so it is pretty different from taking Accutane. Accutane stimulates sebaceous glands but then the skin dries up. ATRA is often used in a topical creme for acne and seems to work. It seems to me the most likely explanation for why Accutane helps with acne is the megadose of Accutane disables the sebaceous glands.

ATRA (and/or 13-cis-retinoic acid) tends to do a similar thing with hair, in the higher than normal amounts present from Hypervitaminosis A it makes it growth thicker on the body and head but then cause hairloss on the head over time. When taken as a cancer drug it can do this:

"You could lose all your hair. This includes your eyelashes, eyebrows, underarm, leg and sometimes pubic hair. Your hair will usually grow back once treatment has finished but it is likely to be softer. It may grow back a different colour or be curlier than before."

Tretinoin (Vesanoid, ATRA) | Cancer information | Cancer Research UK

I'm coming up to 1.5 years on a low VA diet and I'm yet to see a reduction of oily skin. I may still have Hypervitaminosis A though, my blood test at 12 months indicated I still had a long way to go. I've seen a 100% cure of cracked lips and a 95% cure of seb derm though.

My posts at the Genereux forum tend to get more dislikes than likes these days when all I've been doing is making a sincere effort to provide helpful and accurate information. It's the same everywhere though, people don't like those that question the narrative of the group that they identify with. These same people will post questions where they are concerned about the carotenoids in something like beans or olive oil, highly orthorexic thinking. A low VA diet is very simple and there is only a limited number of foods that need to be excluded (most of which we would rather not consume anyway lol), it just has to be followed for a long time.

 

[Troubles]

If you don't have anything to hide and you're a good person, why would you just suddenly ban someone who asked a good question? I mean what is so wrong about my question that you have to ban me, seriously. How could you believe anything that Grant says when he acts this way.

 

[Randle Cyclist]

Sites that ban people for asking questions often have the makings of a cult. Questions should be encouraged as the answers can help solidify one's position or argument, helping to assuage any concerns others might have. Being expected to blindly accept a leader's doctrine is a major red flag. Radical diets seem to foster this sort of cultish rigidity, from carnivore to fruitarianism to Vit A avoidance. Deviate from the group and you're out.

 

[puddleduck]

Randle Cyclist - At Grant’s site questions and differences of opinion (and practically unmoderated discussions) are are allowed and encouraged. It doesn’t have a cult vibe yet. :P

Troubles was banned for accusing Grant of trying to change the subject when he requested Troubles, and others, keep the forum respectful in a thread where rudeness was rampant.

(For those curious, here is the thread in question: Calcium - Page 4)


Tim333 - No downvotes from me, Tim! I appreciate your perspective and knowledge.

 

[mrchibbs]

Sites that ban people for asking questions often have the makings of a cult. Questions should be encouraged as the answers can help solidify one's position or argument, helping to assuage any concerns others might have. Being expected to blindly accept a leader's doctrine is a major red flag. Radical diets seem to foster this sort of cultish rigidity, from carnivore to fruitarianism to Vit A avoidance. Deviate from the group and you're out.

We can all get caught up in certain rigid mindsets, and banning people etc. I think in the early days of the "RP community" five or more years ago, there was this type of defensive attitude and simplistic interpretations of Ray's ideas. We've grown a lot over the years however. Thankfully, RPF, although not perfect, is a pretty tolerant place where we try to be as open and anti-authoritarian as possible. At least that's an ideal we should strive for. At the best times, this forum is a compassionate place where people can help and get support, and explore ideas without shame or conflict.

I think Grant made some good observations, and we should discuss about Vitamin A or anything to that matter. I've just found that sometimes people hold on so firmly to certain premises (vitamin A is a toxin, estrogen is always bad, fatty acids are terrible etc.) that it is impossible to have any discussion from that starting point. One of my favourite quotes from Ray is when he said that we must accept all knowledge is tentative, and in turn that should make us humble about what we think know.

 

[Troubles]

Randle Cyclist - At Grant’s site questions and differences of opinion (and practically unmoderated discussions) are are allowed and encouraged. It doesn’t have a cult vibe yet. :P

Troubles was banned for accusing Grant of trying to change the subject when he requested Troubles, and others, keep the forum respectful in a thread where rudeness was rampant.

(For those curious, here is the thread in question: Calcium - Page 4)


Tim333 - No downvotes from me, Tim! I appreciate your perspective and knowledge.

You are wrong. Grant banned me because that way I won't be able to answer his stupid answer to my question. His answer was "I think you are confusing sebaceous glands being destroyed, and no longer being able to properly moisturize the skin, with being “cured.” This answer doesn't make any sense because even 10mg dose of isotretinoin taken just twice a week makes my oil production stop completely in three days. So Grant is suggesting that 10mg of isotretinoin destroys my sebaceous glands in three days, seriously? And why does the oil come back right after I stop taking isotretinoin? Are my sebaceous glands regenerated in less than a week? This is the kind of craziness that is going on in Grant's forum, what ever Grant says is the unquestioned truth and if you so even a hint of doubt, you're out.

Anyways I've been a lot more happier after getting banned from that toxic forum, I feel like I got out of some moldy dark dungeon into the sun again.

 

[tim333]

Randle Cyclist - At Grant’s site questions and differences of opinion (and practically unmoderated discussions) are are allowed and encouraged. It doesn’t have a cult vibe yet. :P

Troubles was banned for accusing Grant of trying to change the subject when he requested Troubles, and others, keep the forum respectful in a thread where rudeness was rampant.

(For those curious, here is the thread in question: Calcium - Page 4)


Tim333 - No downvotes from me, Tim! I appreciate your perspective and knowledge.

Thank you Puddleduck, I appreciate your posts too.

 

[Amazoniac]

- Why 11-cis-Retinal? Why Not 7-cis-, 9-cis-, or 13-cis-Retinal in the Eye?

 

[md_a]

I found this blog and I find it interesting in terms of the idea of aldehyde toxicity from an dehydrogenase system unable to function properly due to lack of cofactors.

My Blog — Eric Levinson Health Coaching

From: Eric Justin Levinson

Folic acid is known to prevent birth defects.

How does one become deficient?

Methanol and formaldehyde require the same dehydrogenase enzymes to be oxidized into formic acid.

Retinol > retinaldehyde > retinoic acid (vitamin A)

Alcohol > acetaldehyde > acetic acid

Same pathway.

The acid forms require a oxidizing agent to eliminate them safely.

Acetic acid requires a mineral base.

Retinoic acid requires taurine.

Formic acid requires folinic acid.

Folinic acid is the fully reduced folic acid, ready for the body to use.

Formaldehyde/methanol exposure is going to deplete folic acid. And aldehydes, including formaldehyde, acetaldehyde, and retinaldehyde cause birth defects.

Here we have a study that proved folic acid also prevented birth defects caused by retinoic acid.

“Administration of retinoic acid at all doses resulted in statistically significant decreases in mean fetal weight and mean fetal height and the increase in mortality rate, and caused se- vere ultrastructural damages in Meckel’s cartilage. Folic acid administration prevented the decrease in mean fetal weight and height of the embryos treated with retinoic acid of 40 mg/kg.”

http://www.journal.med.tohoku.ac.jp/2051/TJ2051_04.pdf

Now you know why, women supplementing with vitamin A in a prenatal multi, in addition to their dietary and fortified vitamin A, need very high doses of folic acid to compensate for the dangers of the high vitamin A intake.

...

Retinol is actually "vitamin A alcohol," and causes similar problems as alcohol, including birth defects known as fetal retinoid syndrome.

It's metabolized by the same dehydrogenase enzymes as alocohol and methanol, which creates aldehydes.

Much better would be to support the dehydrogenase system and eliminate the build up of toxic aldehydes.


Targeting Aldehyde Dehydrogenase 2: New Therapeutic Opportunities

...

When our dehydrogenase system is inhibited, we build up aldehydes, like vitamin A, which cause headaches.

Our dehydrogenase turns alcohol into acetaldehyde, and that gets turned into acetic acid.

Same pathway for vitamin A and formaldehyde.


Retinaldehyde is made when we split a beta-carotene molecule in half, or when vitamin A alcohol (retinol) is metabolized into an aldehyde in the process of eliminating it form the body.


Some of our most important neurotransmitters like dopamine, and other important chemicals like pyruvate, depend on this system to prevent the build up of aldehydes that are created when these chemicals are used up in the body.[1]

However, dehydrogenase is a finite resource.

It is easily overwhelmed by to much aldehyde exposure from things like air pollution, or when they build up in the body.

The resources required to make it are also easily depleted.

Like zinc, for example.[2]

Now you know why everyone with coronavirus does so much better when they supplement with zinc.

Because without zinc, they can't make dehydrogenase to get rid of the aldehydes that are damaging their lungs.

Aldehydes are also released from combustion of fossil fuels, including natural gas from our stoves.

Interestingly, ethanol blend fuels, like the 10% ethanol we use in the US, releases more aldehydes than straight petroleum gasoline.

Adding ethanol increases the aldehyde emissions 40%![3]

So what does the EPA say about inhalation of aldehydes?

Aldehydes constrict airway passages, and "can also damage cells lining the airways, prompting white blood cells to enter the lungs."[4]

What happens when white blood cells enter the lungs?

Well, that's pneumonia.[5]

And all those aldehydes our bodies make, one of the ways we get rid of them is by our breath.

That's why people have that distinctive breath in the morning after a long night of drinking.

It's aldehydes.


Our dehydrogenase turns alcohol into acetaldehyde.

Methanol becomes formaldehyde.

Retinol becomes retinaldehyde.

That's the process our bodies use to break down retinoids, also known as vitamin A and beta carotene.

So if we are consuming high amounts of retinoids in our diets, we are depleting that vital resource our bodies produce to protect us from the aldehydes from air pollution.

So, many sources of aldehydes in our air cannot be avoided, neither can our endogenous aldehydes.

We can learn to effectively limit them in our diets.

And then our zinc supplementation can do much more to protect our lungs from air pollution.

My Blog — Eric Levinson Health Coaching

Dehydrogenase - Wikipedia

 

[somuch4food]

@md_a Great find! I like the idea of an overwhelmed system better than outright toxicity.

 

[md_a]

...Aldehyde toxicity is characterized by cell-localized, micronutrient deficiencies in sulfur-containing antioxidants, thiamine (B1), pyridoxine (B6), folate, Zn2+, possibly Mg2+, and retinoic acid, causing oxidative stress and a cascade of metabolic disturbances. Aldehydes also react with selective cytosolic and membrane proteins in the cell of origin; then some types migrate to damage neighboring cells. Reactive aldehydes also form adducts with DNA, selectively mutating bases and inducing strand breakage. This article reviews the relevant genomic, biochemical, and nutritional literature, which supports the central hypothesis that most ASD symptoms are consistent with symptoms of aldehyde toxicity. The hypothesis represents a paradigm shift in thinking and has profound implications for clinical detection, treatment, and even prevention of ASD. Insight is offered as to which neurologically afflicted children might successfully be treated with micronutrients and which children are unlikely to be helped. The aldehyde toxicity hypothesis likely applies to other neurological disorders.

...

In addition to the direct reactions between aldehydes and micronutrients, the alcoholism literature suggests that alternative mechanisms may induce a deficiency in the retinoic acid form of vitamin A particularly in those individuals with heritable forms of alcoholism. Ethanol is known to compete directly for the retinol-binding site on the ADHs involved in the rate-limiting step of retinol oxidation, thereby decreasing the amount of retinal and retinoic acid that is ultimately produced. Because retinoic acid controls the regulation of fetal development, neuronal growth, differentiation, and limb morphogenesis, ethanol-induced deficiencies of retinoic acid are believed to play a major role in fetal alcohol syndrome disorder (FASD).50,51 Retinoic acid also plays a major role in epigenetic changes in the cell.49 In many ways, the symptoms of FASD mimic those of the complex form of ASD, suggestive of a problem during embryonic development.52 Moreover, many ASD children suffer from hypovitaminosis A,53,54 which is commonly attributed to highly restrictive diets or to intestinal malabsorption. However, some reports indicate that the same children do not have night blindness,53 and some reports suggest that ASD symptoms are reduced by retinol treatment.54 The lack of night blindness in ASD cases of vitamin A deficiencies suggests that retinal is present, but conversion to retinoic acid is blocked. An accumulation of retinal would have the same toxicity consequences as other endogenous aldehydes but with the added problem that a deficiency in retinoic acid would disrupt the retinoic acid response element (RARE)-dependent transcription of many key proteins in embryonic and neuronal development...

Summary

The many symptoms and divergent theories of ASD are consistent with aldehyde toxicity in which reactive aldehydes accumulate as a consequence of errors associated with genes intended to oxidize, reduce, or otherwise neutralize aldehydes. No matter the source(s) of the accumulated aldehydes, all share a reactive chemical group, which inflicts similar types of intracellular damage, but also suggests that a common treatment plan will be beneficial to many with ASD. Aldehydes induce localized micronutrient deficiencies initiating a cascade of metabolic disturbances in hundreds of metabolic pathways, cause oxidative stress, inactivate proteins by adduct formation, and bind to DNA, ultimately causing mutations and strand breakage. These effects of aldehyde toxicity explain all of the current genetic and biochemical theories of ASD in the medical literature. In addition to damage done by lipid peroxidation-generated aldehydes, already recognized by some experts in ASD,84–87 the central hypothesis expands to other types of endogenous and exogenous aldehydes. The aldehyde toxicity hypothesis has profound implications for early clinical detection and treatment of ASD as well as its prevention. Due to the high risk of permanent, irreversible cellular damage, time is of the essence for treating aldehyde toxicity. Treatment for aldehyde toxicity is similar to nutritional plans already advocated in the orthomolecular community76 but with a few additional features: (1) one or more sulfur-containing antioxidants are essential to neutralize reactive aldehydes and (2) a broad spectrum of micronutrients, with a special emphasis on B6, Zn2+, B1, Mg2+, folate, and retinol, should be included, irrespective of results from currently available, but inadequate, clinical testing. Such a treatment plan appears to be the best option for treating ASD now, until the genetics of ASD is better understood, and targeted therapies can be implemented. The hypothesis likely applies to many other neurological disorders, such as schizophrenia, with the major differences among disorders being the source, concentration, and reactivity of the accumulated aldehydes.

The Pivotal Role of Aldehyde Toxicity in Autism Spectrum Disorder: The Therapeutic Potential of Micronutrient Supplementation

 

[Amazoniac]

I found this blog and I find it interesting in terms of the idea of aldehyde toxicity from an dehydrogenase system unable to function properly due to lack of cofactors.

My Blog — Eric Levinson Health Coaching

From: Eric Justin Levinson

Folic acid is known to prevent birth defects.

How does one become deficient?

Methanol and formaldehyde require the same dehydrogenase enzymes to be oxidized into formic acid.

Retinol > retinaldehyde > retinoic acid (vitamin A)

Alcohol > acetaldehyde > acetic acid

Same pathway.

The acid forms require a oxidizing agent to eliminate them safely.

Acetic acid requires a mineral base.

Retinoic acid requires taurine.

Formic acid requires folinic acid.

Folinic acid is the fully reduced folic acid, ready for the body to use.
View attachment 18299
Formaldehyde/methanol exposure is going to deplete folic acid. And aldehydes, including formaldehyde, acetaldehyde, and retinaldehyde cause birth defects.

Here we have a study that proved folic acid also prevented birth defects caused by retinoic acid.

“Administration of retinoic acid at all doses resulted in statistically significant decreases in mean fetal weight and mean fetal height and the increase in mortality rate, and caused se- vere ultrastructural damages in Meckel’s cartilage. Folic acid administration prevented the decrease in mean fetal weight and height of the embryos treated with retinoic acid of 40 mg/kg.”

http://www.journal.med.tohoku.ac.jp/2051/TJ2051_04.pdf

Now you know why, women supplementing with vitamin A in a prenatal multi, in addition to their dietary and fortified vitamin A, need very high doses of folic acid to compensate for the dangers of the high vitamin A intake.

...

Retinol is actually "vitamin A alcohol," and causes similar problems as alcohol, including birth defects known as fetal retinoid syndrome.

It's metabolized by the same dehydrogenase enzymes as alocohol and methanol, which creates aldehydes.

Much better would be to support the dehydrogenase system and eliminate the build up of toxic aldehydes.


Targeting Aldehyde Dehydrogenase 2: New Therapeutic Opportunities

...

When our dehydrogenase system is inhibited, we build up aldehydes, like vitamin A, which cause headaches.

Our dehydrogenase turns alcohol into acetaldehyde, and that gets turned into acetic acid.

Same pathway for vitamin A and formaldehyde.


Retinaldehyde is made when we split a beta-carotene molecule in half, or when vitamin A alcohol (retinol) is metabolized into an aldehyde in the process of eliminating it form the body.


Some of our most important neurotransmitters like dopamine, and other important chemicals like pyruvate, depend on this system to prevent the build up of aldehydes that are created when these chemicals are used up in the body.[1]

However, dehydrogenase is a finite resource.

It is easily overwhelmed by to much aldehyde exposure from things like air pollution, or when they build up in the body.

The resources required to make it are also easily depleted.

Like zinc, for example.[2]

Now you know why everyone with coronavirus does so much better when they supplement with zinc.

Because without zinc, they can't make dehydrogenase to get rid of the aldehydes that are damaging their lungs.

Aldehydes are also released from combustion of fossil fuels, including natural gas from our stoves.

Interestingly, ethanol blend fuels, like the 10% ethanol we use in the US, releases more aldehydes than straight petroleum gasoline.

Adding ethanol increases the aldehyde emissions 40%![3]

So what does the EPA say about inhalation of aldehydes?

Aldehydes constrict airway passages, and "can also damage cells lining the airways, prompting white blood cells to enter the lungs."[4]

What happens when white blood cells enter the lungs?

Well, that's pneumonia.[5]

And all those aldehydes our bodies make, one of the ways we get rid of them is by our breath.

That's why people have that distinctive breath in the morning after a long night of drinking.

It's aldehydes.


Our dehydrogenase turns alcohol into acetaldehyde.

Methanol becomes formaldehyde.

Retinol becomes retinaldehyde.

That's the process our bodies use to break down retinoids, also known as vitamin A and beta carotene.

So if we are consuming high amounts of retinoids in our diets, we are depleting that vital resource our bodies produce to protect us from the aldehydes from air pollution.

So, many sources of aldehydes in our air cannot be avoided, neither can our endogenous aldehydes.

We can learn to effectively limit them in our diets.

And then our zinc supplementation can do much more to protect our lungs from air pollution.

My Blog — Eric Levinson Health Coaching

Dehydrogenase - Wikipedia

I came across the last publication posted ('Why 11-cis poisonal?') after trying to find out the specific coloration of the major natural poisonoids because it could be an indicator for the limitation.

- Limulus retinal potential | SMCM

"Retinaldehyde itself is very light yellow in color."​

For example, if the person consumes pro-poison A carotenoids, feels off but without developing the characteristic orange skin tone, it would be down and the stream. However, it soon became clear that it's not worth the bother because it doesn't exclude the possibility of issues before and after acted upod, the concentration needed to cause problems might not trigger manifestations (if we was to ingest equivalent amounts of poisonol to those that we tolerate ethanol, we would be hospitalized), the aldehydes probably don't remain moving around freely for long or without interacting with other compounds that might affect the color.

Poisonal oxidase and poisonal dehydrogenase are different. If we ask Brenda what she thinks, she will confirm ('show all'):

- BRENDA - Information on EC 1.2.1.3 - aldehyde dehydrogenase (NAD+)
- BRENDA - Information on EC 1.2.1.36 - retinal dehydrogenase

- BRENDA - Information on EC 1.2.3.1 - aldehyde oxidase
- BRENDA - Information on EC 1.2.3.11 - retinal oxidase​

Such oxidase seems to be a backup system that doesn't require the cofactor, similar to what happens with ethanol/poisonol:

- Advanced Nutrition and Human Metabolism (978-1-133-10405-6)

Spoiler

"Ethyl alcohol (ethanol) is neither a carbohydrate nor a lipid. Though empirically ethanol’s structure (CH3— CH2—OH) most closely resembles a carbohydrate, its metabolism most closely resembles fatty acid catabolism. We have chosen to review it in this chapter for several reasons. First, it is a common dietary component, being consumed in the form of alcoholic beverages such as beer, wines, and distilled spirits. Second, the pathways that oxidize ethyl alcohol also oxidize (or detoxify) other exogenous substances in the body. Although ethanol is not a “natural” nutrient, it does have caloric value (its calories are “empty,” that is, devoid of beneficial nutrients). Each gram of ethanol yields 7 kcal, and ethanol may account for up to 10% of the total energy intake of moderate consumers and up to 50% for alcoholics. Because of its widespread consumption and relatively high caloric potency, it commands attention in a nutrition textbook."

"Ethanol is readily absorbed through the entire gastrointestinal tract. It is transported unaltered in the bloodstream and then oxidatively degraded in tissues, primarily the liver, first to acetaldehyde and then to acetate. In tissues other than the liver, as well as in the liver itself, the acetate subsequently is converted to acetyl-CoA and oxidized via the TCA cycle. At least three enzyme systems are capable of ethanol oxidation:

• alcohol dehydrogenase (ADH)
• the microsomal ethanol oxidizing system (MEOS; also known as the cytochrome P-450 system)
• catalase, in the presence of hydrogen peroxide

Of these, the catalase-H2O2 system is the least active, probably accounting for <2% of in vivo ethanol oxidation. Therefore, we will not discuss the catalase system further. Nearly all ingested ethanol is oxidized by hepatic (and, to some extent, gastric) alcohol dehydrogenase and hepatic microsomal cytochrome P-450 systems."

"ADH is a soluble enzyme functioning in the cytosol of hepatocytes. It is an ordinary NAD+-requiring dehydrogenase and is known to be able to oxidize ethanol to acetaldehyde. The NADH formed by the reaction can be oxidized by mitochondrial electron transport by way of the NADH shuttle systems (see Chapter 3), thereby giving rise to ATP formation by oxidative phosphorylation. The Km of alcohol dehydrogenase for ethanol is approximately 1 millimolar, or about 5 mg/dL." "This means that at this cellular concentration of ethanol, ADH is functioning at half its maximum velocity. At concentrations three or four times the Km, the enzyme is saturated with the ethanol substrate and is catalyzing at its maximum rate. Concentrations of ethanol in the cell more than four times the Km level cannot be completely oxidized by ADH."

"Because ethanol is an exogenous dietary ingredient, there is no “normal” concentration of ethanol in the cells or the bloodstream. The so-called toxic level of blood ethanol, however, is considered to be in the range of 50 to 80 mg/dL and is defined by its pharmacological actions. The high lipid solubility of ethanol allows it to passively enter cells with ease. If its cellular concentration reaches a level even one-third or one-fourth of that of the blood at toxic levels, ADH becomes saturated by the substrate and will be functioning at its maximum velocity. The excess, or “spillover,” ethanol then must be metabolized by alternate systems, the most important of which is the microsomal ethanol oxidizing system (MEOS), described next. The depletion of NAD+ brought about by the high level of activity of ADH can also force the shift to the microsomal system, which does not require NAD+ for its oxidative reactions. The depletion of NAD+alters the NAD+: NADH ratio and impairs NAD+-requiring reactions such as the TCA cycle, gluconeogenesis, and fatty acid oxidation. The buildup of acetyl-CoA encourages fatty acid synthesis in the liver and with time can lead to TAG accumulation in this organ [40]."

"Alcohol dehydrogenase is also active in gastric mucosal cells. Interestingly, there appears to be a significant gender difference in the level of its activity in these cells. Young (premenopausal) females develop higher blood alcohol levels than male counterparts with equal consumption and consequently display a lower tolerance for alcohol and are at greater risk of toxic effects in the liver. The lower level of alcohol dehydrogenase activity in the female gastric mucosa is believed to account for this observation [48,49]."

"Despite its name, the microsomal ethanol oxidizing system (MEOS) is able to oxidize a wide variety of compounds in addition to ethanol, including fatty acids, aromatic hydrocarbons, steroids, and barbiturate drugs. The oxidation occurs through a system of electron transport, similar to the mitochondrial electron transport system described in detail in Chapter 3. Because the MEOS is microsomal (isolated ER) and associated with the smooth endoplasmic reticulum, it is sometimes referred to as the microsomal electron transport system. Another distinction of the system is its requirement for a special cytochrome called cytochrome P-450, which acts as an intermediate electron carrier. Cytochrome P-450 is not a single compound but rather exists as a family of structurally related cytochromes, the members of which share the property of absorbing light that has a wavelength of 450 nm."

"Ethanol oxidation by the MEOS involves several linked oxidation reactions of NADPH, FAD, FMN, and cytochrome P-450 that result in the simultaneous oxidation of reduced cytochrome P-450 and oxidation of ethanol to acetaldehyde by molecular oxygen. Because two substrates are oxidized concurrently, the enzymes involved in the oxidations are commonly called mixed-function oxidases. Both oxygen atoms are reduced to H2O, and therefore two H2O molecules are formed in the reactions." "Acting as carriers of electrons from NADPH to oxygen are FAD, FMN, and a cytochrome P-450 system."

"An important feature of the MEOS is that certain of its enzymes, including the cytochrome P-450 units, are inducible by ethanol—particularly at higher concentrations of ethanol. With increased synthesis of these substances, the hepatocytes can metabolize ethanol much more effectively, thereby establishing a state of metabolic tolerance. Compared with a normal (nondrinking or light-drinking) subject, an individual in a state of metabolic tolerance to ethanol can ingest larger quantities of the substance before showing the effects of intoxication. When enzyme induction occurs, however, it can also accelerate the metabolism of other substances metabolized by the microsomal system. In other words, tolerance to ethanol induced by heavy drinking can render a person tolerant to other substances as well."

"The well-known consequences of alcoholism—fatty liver, hepatic disease (cirrhosis), lactic acidosis, and metabolic tolerance— can be explained by the manner in which ethanol is metabolized. Basically, the consequences of excessive alcohol intake are explainable by metabolic effects of (1) acetaldehyde toxicity, (2) elevated NADH:NAD+ ratio, (3) metabolic competition, and (4) induced metabolic tolerance."

"Both the ADH and MEOS routes of ethanol oxidation produce acetaldehyde, which is believed to exert direct adverse effects on metabolic systems. For example, acetaldehyde is able to attach covalently to proteins, forming protein adducts. Should the adduct involve an enzyme, the activity of that enzyme could be impaired. Acetaldehyde has also been shown to impede the formation of microtubules in liver cells and to cause the development of perivenular fibrosis, either of which is believed to initiate the events leading to cirrhosis. These and other possible adverse effects of acetaldehyde are reviewed by Lieber [51]. Alcoholic cirrhosis was once thought to be caused by malnutrition because the drinker satisfied his or her caloric needs with the empty calories of alcohol at the expense of a nutritionally balanced diet. In view of the effect of high levels of acetaldehyde on hepatocyte structure and function, however, chronic overindulgence is now known to cause cirrhosis even when nutritional deficiency is absent and the alcohol is co-ingested with an enriched diet."

"The oxidation of ethanol increases the concentration of NADH at the expense of NAD+, thereby elevating the NADH:NAD+ ratio. This occurs because both ADH and acetaldehyde dehydrogenase use NAD+ as a cosubstrate. NADH is an important regulator of certain dehydrogenase reactions. The rise in concentration of NADH represents an overproduction of reducing equivalents, which in turn acts as a signal for a metabolic shift toward reduction—namely, hydrogenation. Such a shift can account for the fatty liver (through the anabolic activity producing fatty acids) and lactic acidemia (high blood-lactate levels resulting from increased reduction of pyruvate to lactic acid) that often accompany alcoholism. For example, lactic acidemia can be attributed in part to the direct effect of NADH in shifting the lactate dehydrogenase (LDH) reaction toward the formation of lactate. The reaction, which follows, is driven to the right by the high concentration of NADH:

Pyruvate + NADH + H+ ← LDH → Lactate + NAD+​

Lipids accumulate in most tissues in which ethanol is metabolized, resulting in fatty liver, fatty myocardium, fatty renal tubules, and so on. The mechanism appears to involve both increased lipid synthesis and decreased lipid removal and can be explained in part by the increased NADH:NAD+ ratio. As NADH accumulates, it slows dehydrogenase reactions of the TCA cycle, such as the isocitrate dehydrogenase and α-ketoglutarate dehydrogenase reactions, thereby slowing the overall activity of the cycle. This results in an accumulation of citrate, which positively regulates acetyl-CoA carboxylase. Acetyl-CoA carboxylase, which converts acetyl-CoA into malonyl-CoA by the attachment of a carboxyl group, is the key regulatory enzyme for the synthesis of fatty acids from acetyl-CoA. The high NADH:NAD+ ratio therefore directs metabolism away from TCA cycle oxidation and toward fatty acid synthesis."

"Also contributing to the lipogenic effect of alcoholism is the effect of NADH on the glycerophosphate dehydrogenase (GPDH) reaction. This reaction [] favors the reduction of dihydroxyacetone phosphate (DHAP) to glycerol-3-phosphate if NADH concentration is high. Glycerol-3-phosphate provides the glycerol component in the synthesis of triacylglycerols. Therefore, a high NADH:NAD+ ratio stimulates the synthesis of both the fatty acids and the glycerol components of triacylglycerols, contributing to the cellular fat accumulation that develops in alcoholism."

"A rise in NADH concentration also affects the glutamate dehydrogenase (GluDH) reaction [], resulting in impaired gluconeogenesis. The GluDH reaction is extremely important in gluconeogenesis because of the role it plays in the conversion of amino acids to their carbon skeletons by transamination and in the release of their amino groups as NH3. A shift in the reaction toward glutamate because of the elevated NADH depletes the availability of α-ketoglutarate, which is the major acceptor of amino groups in the transamination of amino acids."

"A well-established nutritional problem associated with excessive alcohol metabolism is a deficiency of vitamin A. Two aspects of ethanol interference with normal metabolism probably can account for this problem. One is the effect of ethanol on retinol dehydrogenase, the cytoplasmic enzyme that converts retinol to retinal. Retinal is required for the synthesis of photo pigments used in vision. Retinol dehydrogenase is thought to be identical to ADH, and therefore ethanol competitively inhibits the hepatic conversion of retinol to retinal. In addition to this substrate competition effect, ethanol may interfere with retinol metabolism through induced metabolic tolerance."

"As explained earlier, ethanol can induce enzymes of the MEOS, causing an increased rate of metabolism of substrates oxidized by this system. Retinol, like ethanol, spills over into the MEOS when ADH is saturated and NAD+ stores are low because of heavy ingestion of ethanol. Ethanol induction of retinol-metabolizing enzymes then can occur. The specific component of the MEOS known to be induced by heavy consumption of ethanol has been designated cytochrome P-4502E1 (CYP2E1). Although induction accelerates the hepatic oxidation of retinol, the oxidation product is not retinal but other polar, inert products of oxidation. The hepatic depletion of retinol can therefore be attributed to its accelerated metabolism, which is secondary to ethanol induction of a metabolizing enzyme. In effect, the alcoholic subject becomes tolerant to vitamin A, necessitating a higher dietary intake of the vitamin to maintain normal hepatocyte concentrations."

I find it suspicious that we're able to metabolize large amounts of acetaldehyde at once but be overwhelmed by relatively small amounts of poisonal (although poisonoids cycle). It must be a trigger for reactions that are depleting rather than direct consumption.

- Aldehyde Dehydrogenases and Their Role in Carcinogenesis (Table 1-4)

 

[Tarmander]

If you don't have anything to hide and you're a good person, why would you just suddenly ban someone who asked a good question? I mean what is so wrong about my question that you have to ban me, seriously. How could you believe anything that Grant says when he acts this way.

He isn't charging for anything.
He gives away his books and his time for free.
Try not crapping on the floor of someone's house the first time you get invited in

 

[Troubles]

He isn't charging for anything.
He gives away his books and his time for free.
Try not crapping on the floor of someone's house the first time you get invited in

Grant, shut up. I wasn't implying that you are getting financial benefits from this. I got out from that hell and I'm not coming back, so just let it go.

 

[somuch4food]

Grant, shut up. I wasn't implying that you are getting financial benefits from this. I got out from that hell and I'm not coming back, so just let it go.

You should explore this forum before shouting nonsense. Tarmander is a legit forum member.

I think you are the one not letting go and holding a grudge.

 

[charlie]

Grant, shut up. I wasn't implying that you are getting financial benefits from this. I got out from that hell and I'm not coming back, so just let it go.

Consider yourself warned. If you want to act respectfully you are more then welcome to stay. Abusing our members will not be tolerated.

 

[Recoen]

For everyone who seems to have this issue with vitamin A, have you looked into glucuronidation?

 

[tim333]

I found this blog and I find it interesting in terms of the idea of aldehyde toxicity from an dehydrogenase system unable to function properly due to lack of cofactors.

My Blog — Eric Levinson Health Coaching

From: Eric Justin Levinson

Folic acid is known to prevent birth defects.

How does one become deficient?

Methanol and formaldehyde require the same dehydrogenase enzymes to be oxidized into formic acid.

Retinol > retinaldehyde > retinoic acid (vitamin A)

Alcohol > acetaldehyde > acetic acid

Same pathway.

The acid forms require a oxidizing agent to eliminate them safely.

Acetic acid requires a mineral base.

Retinoic acid requires taurine.

Formic acid requires folinic acid.

Folinic acid is the fully reduced folic acid, ready for the body to use.
View attachment 18299
Formaldehyde/methanol exposure is going to deplete folic acid. And aldehydes, including formaldehyde, acetaldehyde, and retinaldehyde cause birth defects.

Here we have a study that proved folic acid also prevented birth defects caused by retinoic acid.

“Administration of retinoic acid at all doses resulted in statistically significant decreases in mean fetal weight and mean fetal height and the increase in mortality rate, and caused se- vere ultrastructural damages in Meckel’s cartilage. Folic acid administration prevented the decrease in mean fetal weight and height of the embryos treated with retinoic acid of 40 mg/kg.”

http://www.journal.med.tohoku.ac.jp/2051/TJ2051_04.pdf

Now you know why, women supplementing with vitamin A in a prenatal multi, in addition to their dietary and fortified vitamin A, need very high doses of folic acid to compensate for the dangers of the high vitamin A intake.

...

Retinol is actually "vitamin A alcohol," and causes similar problems as alcohol, including birth defects known as fetal retinoid syndrome.

It's metabolized by the same dehydrogenase enzymes as alocohol and methanol, which creates aldehydes.

Much better would be to support the dehydrogenase system and eliminate the build up of toxic aldehydes.


Targeting Aldehyde Dehydrogenase 2: New Therapeutic Opportunities

...

When our dehydrogenase system is inhibited, we build up aldehydes, like vitamin A, which cause headaches.

Our dehydrogenase turns alcohol into acetaldehyde, and that gets turned into acetic acid.

Same pathway for vitamin A and formaldehyde.


Retinaldehyde is made when we split a beta-carotene molecule in half, or when vitamin A alcohol (retinol) is metabolized into an aldehyde in the process of eliminating it form the body.


Some of our most important neurotransmitters like dopamine, and other important chemicals like pyruvate, depend on this system to prevent the build up of aldehydes that are created when these chemicals are used up in the body.[1]

However, dehydrogenase is a finite resource.

It is easily overwhelmed by to much aldehyde exposure from things like air pollution, or when they build up in the body.

The resources required to make it are also easily depleted.

Like zinc, for example.[2]

Now you know why everyone with coronavirus does so much better when they supplement with zinc.

Because without zinc, they can't make dehydrogenase to get rid of the aldehydes that are damaging their lungs.

Aldehydes are also released from combustion of fossil fuels, including natural gas from our stoves.

Interestingly, ethanol blend fuels, like the 10% ethanol we use in the US, releases more aldehydes than straight petroleum gasoline.

Adding ethanol increases the aldehyde emissions 40%![3]

So what does the EPA say about inhalation of aldehydes?

Aldehydes constrict airway passages, and "can also damage cells lining the airways, prompting white blood cells to enter the lungs."[4]

What happens when white blood cells enter the lungs?

Well, that's pneumonia.[5]

And all those aldehydes our bodies make, one of the ways we get rid of them is by our breath.

That's why people have that distinctive breath in the morning after a long night of drinking.

It's aldehydes.


Our dehydrogenase turns alcohol into acetaldehyde.

Methanol becomes formaldehyde.

Retinol becomes retinaldehyde.

That's the process our bodies use to break down retinoids, also known as vitamin A and beta carotene.

So if we are consuming high amounts of retinoids in our diets, we are depleting that vital resource our bodies produce to protect us from the aldehydes from air pollution.

So, many sources of aldehydes in our air cannot be avoided, neither can our endogenous aldehydes.

We can learn to effectively limit them in our diets.

And then our zinc supplementation can do much more to protect our lungs from air pollution.

My Blog — Eric Levinson Health Coaching

Dehydrogenase - Wikipedia

Retinol has its own dehydrogenases distinct from any alcohol dehydrogenase.

Scientists misuse the term "retinol dehydrogenase" when describing an ADH that has broad specificity that includes retinol oxidation but there are specific retinol dehydrogenases.

"Occasionally, the literature refers to retinol dehydrogenase as an enzyme that oxidizes retinol in general, such as class IV alcohol dehydrogenase (ADH4), which reportedly is the most efficient retinol oxidation in the human alcohol dehydrogenase (ADH) family.[3][4]"

Retinol dehydrogenase - Wikipedia

All-trans-retinol dehydrogenase:

ENZYME entry 1.1.1.105

vs

Alcohol dehydrogenase

ENZYME entry 1.1.1.1