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

[mrchibbs]

The thing is,much Parameters get changed by Genereux's Diet,which is clean eating with very low allergen Load.It could be these confounding factors.Also,if you have a lack of Co-factors,or excess of whatever,especially simply too much A,which impinges onto your A-metabolism,like bistecca noted,can explain the improvements of Retinol-eXorcism.But it doesnt proof that Retinol is an evironmental Poison or an Animaltoxin.I saw pictures of Mouse pups,the malformations induced by lack and overexposure of A are both obvious.A is real,Beta Carotin is fake,and dosage matters.

I’ve always thought this! VA deficient diets are typically low allergen, low PUFAs, much like a carnivore diet, and these things do more to explain benefits than VA depletion, it seems

 

[bistecca]

Of course it is your choice to ignore the large amount of anecdotal evidence that can be found in this thread alone. Theory must find models for successful experiments, not vice versa.

I'm not ignoring evidence. I'm simply asking someone to distill the "real" evidence in the 318 previous pages of this thread from the anecdotal, which means nothing to anyone who HASN'T experienced it for themselves. I've already read enough of Grants blog and his books and found significant flaws in his logic and false claims (he eats meat but calls his diet "vitamin A free"). If the only evidence being presented is studies in mice which use elevated levels of VA to induce problems, then there is nothing convincing here. You NEED evidence from a wide array of sources with a wide array of approaches to convince anyone other than yourself. Studies in lab rats and anecdotal personal experiences are not enough.

I started huffing my farts last month and my vision improved! You should try it!

 

[LLight]

I'm not ignoring evidence. I'm simply asking someone to distill the "real" evidence in the 318 previous pages of this thread from the anecdotal, which means nothing to anyone who HASN'T experienced it for themselves. I've already read enough of Grants blog and his books and found significant flaws in his logic and false claims (he eats meat but calls his diet "vitamin A free"). If the only evidence being presented is studies in mice which use elevated levels of VA to induce problems, then there is nothing convincing here. You NEED evidence from a wide array of sources with a wide array of approaches to convince anyone other than yourself. Studies in lab rats and anecdotal personal experiences are not enough.

I started huffing my farts last month and my vision improved! You should try it!

If you have already made your opinion, why do you need to come in this thread and ask such questions?

 

[Blossom]

Of course it is your choice to ignore the large amount of anecdotal evidence that can be found in this thread alone. Theory must find models for successful experiments, not vice versa.

Personally, I am tired of spending my time on studies over studies to find the solution for my issues in theory. I found the solution in practice, and I am improving week after week, month after month, like many, many others do as well. No other nutritional experiment (and I tried many variants, like many others here) went that well for such an extended period of time. I am happy, I don't need theoretical proof for my well being.

This is exactly how I feel.

 

[mrchibbs]

If you have already made your opinion, why do you need to come in this thread and ask such questions?

He's asking for somebody to sum up the ideas in the thread, which I think is fair.

 

[mrchibbs]

Of course it is your choice to ignore the large amount of anecdotal evidence that can be found in this thread alone. Theory must find models for successful experiments, not vice versa.

Personally, I am tired of spending my time on studies over studies to find the solution for my issues in theory. I found the solution in practice, and I am improving week after week, month after month, like many, many others do as well. No other nutritional experiment (and I tried many variants, like many others here) went that well for such an extended period of time. I am happy, I don't need theoretical proof for my well being.

No one here is discounting anecdotal evidence, that's the bedrock of RPF!

But I think VA is a fascinating topic, and we have to understand it better, and this thread has become so big that perhaps it doesn't really help people in that regard.

 

[LLight]

He's asking for somebody to sum up the ideas in the thread, which I think is fair.

Which has been done. He asks that like it was something due to him, on an inapropriate tone (my impression).

I may be over-reacting perhaps.

 

[mrchibbs]

Which has been done. He asks that like it was something due to him, on an inapropriate tone (my impression).

I may be over-reacting perhaps.

It's all good.

I do think the little summary by @Tarmander is cool, and @Amazoniac references are appreciated, but it'd be nice to have something a little bit more exhaustive..., it is after all a 2 year old thread.

 

[bistecca]

It's all good.

I do think the little summary by @Tarmander is cool, and @Amazoniac references are appreciated, but it'd be nice to have something a little bit more exhaustive..., it is after all a 2 year old thread.

I've also asked numerous questions and posed numerous criticisms which have gone unanswered.. I don't know.. If i found something profound that had changed my understanding of health and nutrition and someone came to the thread asking for a summary of 318 pages(if my mind was made up I would have just ignored the thread) I would be inclined to string together more than 5 sentences to help convince them.

 

[TwiNN]

I've also asked numerous questions and posed numerous criticisms which have gone unanswered.. I don't know.. If i found something profound that had changed my understanding of health and nutrition and someone came to the thread asking for a summary of 318 pages(if my mind was made up I would have just ignored the thread) I would be inclined to string together more than 5 sentences to help convince them.

You said you've read Genereux' books and blog, I don't understand what kind of additional insight you expect from a subjective summary of this thread. If you look for studies, I fear you will have to skim through this thread yourself.

You know, it seems that there is no one here who feels the urge to convince you. If you tried a Genereux-like diet and it didn't work for you, it's fine. But if you want to find out why and want to go into detail, you will have to invest the work for yourself. Why should someone feel obligated to work the evidence out that you request, they're not owing you anything.

You NEED evidence from a wide array of sources with a wide array of approaches to convince anyone other than yourself.

Show me one person who succeeded to undoubtedly convince others that his/her theories about nutrition are correct. You have a plethora of different approaches in the nutrition and diet world, and they are fighting for ages using - what you call - evidence to convince each other. You will find studies for any theory, you will need to read pages over pages and invest hours over hours and you will not get any further. Look around you in this forum alone, how many members are still struggling to find their way?
Yes, Ray Peat convinced me, like some others did before him, and I tried his approach. It didn't completely work for me like I imagined, and I experimented further. I don't care if there are studies undoubtedly showing that milk is beneficial or that liver is more beneficial than a tenderloin steak. It didn't work for me, and I leave it to the nutrition scientists to work their way through the jungle of studies. I have better things to do.

 

[reality]

a lot of problematic foods are cut out in this diet, how does one come to the conclusion that it’s vitamin a that’s the problem?

 

[bistecca]

You said you've read Genereux' books and blog, I don't understand what kind of additional insight you expect from a subjective summary of this thread. If you look for studies, I fear you will have to skim through this thread yourself.

You know, it seems that there is no one here who feels the urge to convince you. If you tried a Genereux-like diet and it didn't work for you, it's fine. But if you want to find out why and want to go into detail, you will have to invest the work for yourself.



Show me one person who succeeded to undoubtedly convince others that his/her theories about nutrition are correct. You have a plethora of different approaches in the nutrition and diet world, and they are fighting for ages using - what you call - evidence to convince each other. You will find studies for any theory, you will need to read pages over pages and invest hours over hours and you will not get any further. Look around you in this forum alone, how many members are still struggling to find their way?
Yes, Ray Peat convinced me, like some others did before him, and I tried his approach. It didn't completely work for me like I imagined, and I experimented further. I don't care if there are studies undoubtedly showing that milk is beneficial or that liver is more beneficial than a tenderloin steak. It didn't work for me, and I leave it to the nutrition scientists to work their way through the jungle of studies. I have better things to do.

>You said you've read Genereux' books and blog,

I did not say I had read the WHOLE blog. I had read enough of his books and blog to call into question his competence or his honesty. He says he is on a Vitamin A free diet but he is also condoning a carnivore diet and is speaking at a carnivore conference this year. I provided evidence that even muscle meat can contain appreciable levels of Vitamin A which would, within the context of a carnivore diet, cause you to potentially EXCEED daily vitamin A recommendations. A carnivore diet, even avoiding organs, could certainly not, if my reference is to be believed(it's a meta study citing numerous other peer reviewed studies) qualify as Vitamin A FREE. No one has addressed this glaring flaw.

>Show me one person who succeeded to undoubtedly convince others that his/her theories about nutrition are correct.

Well I'm here on the RAY PEAT forum because he has done a pretty good job convincing me that his rationale is the most sound. He did this by providing ample evidence from numerous types of science, and it also cohered with the study of anthropology. It makes sense from NUMEROUS angles, not just in rats and on you. Also, Ray has a NUANCED view, while Grant and this thread condone a SIMPLISTIC view, the gist of which seems to be VITAMIN A=BAD. ALL PROBLEMS CAUSED BY VITAMIN A. The simplistic narrative, while compelling to the lazy, is seldom correct.

>it seems that there is no one here who feels the urge to convince you.

And if this is because they're just lazy or they don't actually have the real variety of evidence(other than mouse studies with VA in isolation and their own anecdotal experience), we may never know.

>Why should someone feel obligated to work the evidence out that you request, they're not owing you anything.

Work the evidence out? What does that even mean? I'm not asking the people here to do more science. I'm just asking them to REMEMBER which parts of this thread were the most important in the development of their beliefs, and to cite those posts. Preferably the posts that don't involve rat studies with isolated VA and preferably no personal anecdotes. And if those are the only types of evidence that exist, then admit it.

 

[Amazoniac]

- The mitochondrial PKCδ/retinol signal complex exerts real-time control on energy homeostasis (!)
- Anti-Peat - Grant Genereux's Theory Of Vitamin A Toxicity


- Liver Retinal Reductase and Oxidase Activities in Rats Exposed to Low Environmental Temperature

Spoiler

"Male weanling albino rats of the Holtzman strain, weighing between 40-50 g, were fed a purified retinol-free diet (1) ad lib. throughout the experimental period. After four weeks, when the rats ceased to grow (200-240 g), a daily dose (0.1 ml) of an oil solution of retinyl acetate containing 436.9 mcg (1270 international units) was administered orally for five days.
The rats were then divided into three groups. Group 1 served as zero-time controls and were immediately killed. Group 2 remained at 25 C, while group 3 was placed in a cold room at 5 C. After two weeks, half the rats from groups 2 and 3 were killed. The remainder were maintained for an additional two weeks and were then killed."

"Retinal reductase favors the storage of retinol by the conversion of retinal to retinol and subsequently to retinyl ester, while retinal oxidase causes the utilization of retinal through conversion to retinoic acid."


Differences between groups are simpler to assess here than the meaning of changes due to the confounders. They used poisonyl acetate at a dose that wasn't modest (which we know that it's not physiological) on animals that were consuming decontamined diets and had low reserves, only to discontinue again abruptly before the comparison phase.

It might be possible to prime the enzyme activity towards reduction or oxidation, and tending to continue to perform as such when isolated liver cells was incubated with a different metabolite, they used poisonal to find an activity rate (I don't know if using NADH could reinforce this as well). Since poisonal can have opposite fates, for oxidation to poisonoic acid, they calculated throughout time what wasn't appearing as poisonol and presumed that it went on the other direction. Rats might also be adapted to processing dietary carotenes instead, complicating interpretation further.


But the differences between groups are cool:

"It is known that exposure of rats to a cold environment results in an increased metabolic rate (2) which is accompanied by a decreased growth rate. Increased metabolic rate hastens the depletion of liver retinol whereas a decreased growth rate retards the depletion of retinol from the liver (3)."

"In rats fed a purified retinol-free diet, there is a progressive decrease in liver retinal reductase activity (Fig. 3), whereas retinal oxidase activity showed an increase (Fig. 4)."

"If the changes in enzyme activities in animals exposed to cold are compared with those in control animals, the rate of decrease of retinal reductase and the rate of increase of retinal oxidase are significantly greater in the cold exposed rats. The ratios of retinal reductase activity to retinal oxidase activity were calculated, and are presented in Table I. At zero time, immediately after supplementation with retinyl acetate for five days, the retinal reductase activity far exceeds that of the oxidase. However, the ratio of reductase to oxidase becomes progressively smaller with time on retinol-free diet. If the animals maintained at 25 C are compared with those at 5 C, it is seen that the ratio decreases much more rapidly in the animal exposed to 5 C."

"It is apparent that immediately after supplementation with retinyl acetate for five days (Table I), retinal reductase activity is far greater than that of retinal oxidase. It would seem from these observations that the supply of retinal is in excess and that the rate limiting factor is the conversion of retinal to retinoic acid. Interestingly, maintaining these animals on retinol-free diet results in a gradual decrease in the activity of retinal reductase and an increase in the activity of retinal oxidase." It has a name: d3t0x.

"The decreased retinal reductase activity would result in a decreased rate of conversion of retinol to retinal. This may explain the build-up of liver retinol during a regimen of retinol-free diet (Table II). The concomitant increase in retinal oxidase activity results in a diminished ratio of retinal reductase to retinal oxidase (Table I). Consequently, a greater proportion of retinal formed will be converted to retinoic acid. This may be an adaptive mechanism for maintaining a normal flow of retinal to retinoic acid in the presence of diminished conversion of retinol to retinal."

"Exposure of the animal to a cold environment seems to accelerate these adaptive mechanisms. Both the rate of decrease in retinal reductase and the rate of increase in retinal oxidase are greater in rats exposed to 5 C. After four weeks in the cold, the ratio of retinal reductase to retinal oxidase is less than 1 (Table I), indicating that the rate limiting step for the utilization of retinal is no longer its oxidation to retinoic acid."

"When rats are exposed to cold there is an immediate and sustained increase in metabolic rate (2) which is accompanied by a decreased rate of growth. Johnson and Baumann (3) have shown that these two phenomena have opposing effects on utilization of retinol. Increased metabolic rate results in an increased utilization of retinol, while decreased growth rate is accompanied by decreased utilization. They further show that growth rate is the dominant factor in controlling retinol utilization. The high retinal oxidase activity could presumably be an adaptive response to the elevated metabolic rate as a result of cold exposure. This in itself would result in an increased flow of retinal to retinoic acid. The increased retinoic acid requirement of rats exposed to cold (1) is consistent with this interpretation. Also in line with these observations, Bamji and Sundaresan (27) reported decreased liver storage of retinol in hyperthyroid rats fed retinal, presumably due to increased utilization of retinol."

"To offset the increased requirement imposed by cold exposure, the animal's growth rate is diminished. This may be reflected in the decreased retinal reductase activity in cold exposed rats. In consequence, the flow of retinal to retinoic acid would be limited."

- The effect of steroids on aldehyde oxidation: Studies with indoleacetaldehyde
- The oxidation of retinene (vitamin A1 aldehyde) to vitamin A acid by mammalian steroid-sensitive aldehyde dehydrogenase

Retinene [poisonal] is oxidized irreversibly to vitamin A acid by a pyridine nucleotide-linked aldehyde dehydrogenase present in liver, kidney and small intestine of rabbits. Diethylstilbestrol, dehydroisoandrosterone, estrone and cortisone stimulate the reaction rate at optimal substrate levels; diethylstilbestrol also inhibits when subsubstrate is below 3⋅1o^(-6) M. Progesterone, deoxycorticosterone, testosterone and androsterone inhibit at all substrate levels. The Km [related to affinity] for retinene is 1.4⋅1o^(-6) M. Diethylstilbestrol increases the Km to 7.1⋅1o^(-6) M. This hormone increases the Vmax [related to capacity] a variable amount depending upon the age of the enzyme preparation. Progesterone has little effect on the Km (2.4⋅1o^(-6) M) and lowers the Vmax. The Km for DPN is approx. 1o^(-5) M and is not affected by these steroids or diethylstilbestrol. The energy of activation for retinene is 14.6 kcal/mole and is decreased to 11.9 by stilbestrol and increased to 20 by progesterone. The stimulation produced by diethylstilbestrol is dependent upon the presence of sulfhydryl groups and is reversed by dialyzing away the hormone. The physiological significance of this reaction and its possible hormonal control are discussed.

Getting into the details of cleavage should be useful in figuring out what can go wrong:

- Carotenoid Metabolism and Enzymology

"[The] enzymatic reaction, which yields two retinaldehyde molecules, proceeds in three stages: epoxidation of the 15,15'-double bond, hydration of the double bond leading to ring opening, and oxidative cleavage of the diol formed [132, 133]. During the reaction, a substrate carbocation intermediate is formed, which is stabilized by cation-π interactions with the two aromatic residues in the substrate-binding cleft of BCMO1 [134]. Two oxygen atoms from two different sources are used, molecular oxygen and water; one retinaldehyde incorporates an oxygen atom from dioxygen, and the other retinaldehyde receives an oxygen from water [132]."

Spoiler

"The observation of enhanced Bcmo1 expression in Caco-2 cells by triiodothyronine (T3), which is inhibited by actinomycin D, led Yamaguchi and Suruga [160] to the conclusion that the expression of the Bcmo1 gene might be regulated by T3 at the transcriptional level. However, these researchers were unable to make a clear assessment of whether the observed upregulation was directly a result of thyroid hormone receptor (TR) binding to thyroid hormone response elements (TREs) or due to enhanced PPAR-g transcriptional activity induced by T3 treatment of human intestinal cells. Nevertheless, these findings suggest that T3 might contribute to regulating b-carotene conversion to retinoid in the human small intestine [160]. Similar transcriptional dynamics were observed in experiments performed on rats [161] . Studying the influence of alcohol administration, which results in the decrease of hepatic retinoid levels, these investigators detected increased mRNA levels of Bcmo1, Bcmo2, Ppar-g, Ppar-a, and Tr-b, and the corresponding increases in the protein levels of BCMO2, PPAR-g, and PPAR-a. These findings support the idea that BCMO1 is transcriptionally regulated by PPAR-g in a process that may involve TR-b."

"Flavonoids such as luteolin, quercetin, and rhamnetin [made-up], which have a catechol structure in their B-ring, are remarkably efficient at inhibiting BCMO1 activity in a noncompetitive manner [165, 166]. This may be important for BCMO1 in the intestine, where it may be exposed to these flavonoids."

"Interestingly, an additional potential function for BCMO1 has been proposed recently based on microarray analysis of cadmium-exposed Caenorhabditis elegans and Hepa 1–6 murine hepatoma cells. These studies suggest that Bcmo1 may act as an early cadmium-responsive gene that is highly inducible by cadmium."

"Products of autooxidation formed from free radical attack on carotenoids may be more toxic prooxidants than the original free radicals. As a cause of oxidative stress induction [116 (image)], carotenoid oxidation products may lead to oxidative damage of different cellular components [117, 192], resulting in high cytotoxicity [116, 193]."

- Enzymology of vertebrate carotenoid oxygenases


- Is carotenoid ornamentation linked to the inner mitochondria membrane potential? A hypothesis for the maintenance of signal honesty (relating it to ubiquinone)

- Are aposematic signals honest? A review (on relialbiatwilaty of cues; there's the silly move of invoking this fancy term--that's more erudite than 'erudite' itself--in arguing that pigments are trustworthy when it comes to alarming predators when they should stay away, making strawberries, raspberries, cranberries, cherries, grapes, possibly beetroots, apples, watermelons, and so on, threats)

Spoiler

- Biological roles of fungal carotenoids

 

[Collden]

My impression is that VA plays an important role in immune function and that people feel good on a low-VA diet because it is immunosuppressive. If this is the case it might be that one trades short-term benefits for slow and subtle degeneration over the years. It might be similar to how low-carb and vegan diets also make some people feel better at first by suppressing immunity through restriction of vital nutrients.

No doubt excess VA can be very toxic, but the question is if its possible or likely for someone to accidentally accumulate VA in their body to the point that it actually becomes harmful? I'd say if you eat a balanced diet in tune with your cravings and don't persistently force-feed yourself liver or take supplements its unlikely to happen.

 

[TwiNN]

Work the evidence out? What does that even mean?

I beg your pardon. I am not an english native speaker. I meant: "to let s.o. work for you in order to provide evidence"

I think I made my point of view clear. Just one more thing, that might be of interest for you.

Also, Ray has a NUANCED view, while Grant and this thread condone a SIMPLISTIC view, the gist of which seems to be VITAMIN A=BAD. ALL PROBLEMS CAUSED BY VITAMIN A. The simplistic narrative, while compelling to the lazy, is seldom correct.

For me, Grants simplistic approach helped me to find my way, and I feel better than ever. Maybe I am the rare exception, but glancing at various reports on the internet, I highly doubt that.

However, honestly good luck to you in finding the answers that you seek.

 

[Amazoniac]

People complain of Prolactinese, the language of the future, but aren't bothered by shady nomenclature being employ'd on a daily basis.

Have you noticed how much confusion the name attributed to the enzyme that metabolizes poisonol ↔ poisonal created above? It has different substrates and a reversible action, how can you prioritize one over the other in this case that preference isn't clear? You can name it poisonal reductase, but it could be acting on poisonol by oxidizing it.

A similar problem exists with carbionic annihilase (it hints at the substrate and function, what's going to be doing with the molecule in question). Most people think of it as an enzyme responsible for the (reversible) hydration of waste productide, yet..

- Carbonic anhydrase - Wikipedia

"An anhydrase is defined as an enzyme that catalyzes the removal of a water molecule from a compound, and so it is this "reverse" reaction that gives carbonic anhydrase its name, because it removes a water molecule from carbonic acid."​

 

[Sulcuscentralis]

One thing I am interested in trying is Cholestyramine...trying to find someone who will give me a perscription so I don't have to buy it online at high prices

It binds to fat solubles and other biotoxins way better than beans. Maybe beans on steroids. Could cut down on recovery time.

I found it researching the shoemaker protocol. This guy has a great site for it:

Mold: Are You Moldy?

Cholestyramine: Binders

That stuff is the Jolly Joker of gastro doctors I swear - if other drugs fail that stuff seem to help a lot of different conditions.

 

[bistecca]

- The mitochondrial PKCδ/retinol signal complex exerts real-time control on energy homeostasis (!)
- Anti-Peat - Grant Genereux's Theory Of Vitamin A Toxicity


- Liver Retinal Reductase and Oxidase Activities in Rats Exposed to Low Environmental Temperature

Spoiler

"Male weanling albino rats of the Holtzman strain, weighing between 40-50 g, were fed a purified retinol-free diet (1) ad lib. throughout the experimental period. After four weeks, when the rats ceased to grow (200-240 g), a daily dose (0.1 ml) of an oil solution of retinyl acetate containing 436.9 mcg (1270 international units) was administered orally for five days.
The rats were then divided into three groups. Group 1 served as zero-time controls and were immediately killed. Group 2 remained at 25 C, while group 3 was placed in a cold room at 5 C. After two weeks, half the rats from groups 2 and 3 were killed. The remainder were maintained for an additional two weeks and were then killed."

"Retinal reductase favors the storage of retinol by the conversion of retinal to retinol and subsequently to retinyl ester, while retinal oxidase causes the utilization of retinal through conversion to retinoic acid."


Differences between groups are simpler to assess here than the meaning of changes due to the confounders. They used poisonyl acetate at a dose that wasn't modest (which we know that it's not physiological) on animals that were consuming decontamined diets and had low reserves, only to discontinue again abruptly before the comparison phase.

It might be possible to prime the enzyme activity towards reduction or oxidation, and tending to continue to perform as such when isolated liver cells was incubated with a different metabolite, they used poisonal to find an activity rate (I don't know if using NADH could reinforce this as well). Since poisonal can have opposite fates, for oxidation to poisonoic acid, they calculated throughout time what wasn't appearing as poisonol and presumed that it went on the other direction. Rats might also be adapted to processing dietary carotenes instead, complicating interpretation further.


But the differences between groups are cool:

"It is known that exposure of rats to a cold environment results in an increased metabolic rate (2) which is accompanied by a decreased growth rate. Increased metabolic rate hastens the depletion of liver retinol whereas a decreased growth rate retards the depletion of retinol from the liver (3)."

"In rats fed a purified retinol-free diet, there is a progressive decrease in liver retinal reductase activity (Fig. 3), whereas retinal oxidase activity showed an increase (Fig. 4)."

View attachment 17932 View attachment 17933​

"If the changes in enzyme activities in animals exposed to cold are compared with those in control animals, the rate of decrease of retinal reductase and the rate of increase of retinal oxidase are significantly greater in the cold exposed rats. The ratios of retinal reductase activity to retinal oxidase activity were calculated, and are presented in Table I. At zero time, immediately after supplementation with retinyl acetate for five days, the retinal reductase activity far exceeds that of the oxidase. However, the ratio of reductase to oxidase becomes progressively smaller with time on retinol-free diet. If the animals maintained at 25 C are compared with those at 5 C, it is seen that the ratio decreases much more rapidly in the animal exposed to 5 C."

View attachment 17934​

"It is apparent that immediately after supplementation with retinyl acetate for five days (Table I), retinal reductase activity is far greater than that of retinal oxidase. It would seem from these observations that the supply of retinal is in excess and that the rate limiting factor is the conversion of retinal to retinoic acid. Interestingly, maintaining these animals on retinol-free diet results in a gradual decrease in the activity of retinal reductase and an increase in the activity of retinal oxidase." It has a name: d3t0x.

"The decreased retinal reductase activity would result in a decreased rate of conversion of retinol to retinal. This may explain the build-up of liver retinol during a regimen of retinol-free diet (Table II). The concomitant increase in retinal oxidase activity results in a diminished ratio of retinal reductase to retinal oxidase (Table I). Consequently, a greater proportion of retinal formed will be converted to retinoic acid. This may be an adaptive mechanism for maintaining a normal flow of retinal to retinoic acid in the presence of diminished conversion of retinol to retinal."

View attachment 17935​

"Exposure of the animal to a cold environment seems to accelerate these adaptive mechanisms. Both the rate of decrease in retinal reductase and the rate of increase in retinal oxidase are greater in rats exposed to 5 C. After four weeks in the cold, the ratio of retinal reductase to retinal oxidase is less than 1 (Table I), indicating that the rate limiting step for the utilization of retinal is no longer its oxidation to retinoic acid."

"When rats are exposed to cold there is an immediate and sustained increase in metabolic rate (2) which is accompanied by a decreased rate of growth. Johnson and Baumann (3) have shown that these two phenomena have opposing effects on utilization of retinol. Increased metabolic rate results in an increased utilization of retinol, while decreased growth rate is accompanied by decreased utilization. They further show that growth rate is the dominant factor in controlling retinol utilization. The high retinal oxidase activity could presumably be an adaptive response to the elevated metabolic rate as a result of cold exposure. This in itself would result in an increased flow of retinal to retinoic acid. The increased retinoic acid requirement of rats exposed to cold (1) is consistent with this interpretation. Also in line with these observations, Bamji and Sundaresan (27) reported decreased liver storage of retinol in hyperthyroid rats fed retinal, presumably due to increased utilization of retinol."

"To offset the increased requirement imposed by cold exposure, the animal's growth rate is diminished. This may be reflected in the decreased retinal reductase activity in cold exposed rats. In consequence, the flow of retinal to retinoic acid would be limited."

- The effect of steroids on aldehyde oxidation: Studies with indoleacetaldehyde
- The oxidation of retinene (vitamin A1 aldehyde) to vitamin A acid by mammalian steroid-sensitive aldehyde dehydrogenase

​

Getting into the details of cleavage should be useful in figuring out what can go wrong:

- Carotenoid Metabolism and Enzymology

"[The] enzymatic reaction, which yields two retinaldehyde molecules, proceeds in three stages: epoxidation of the 15,15'-double bond, hydration of the double bond leading to ring opening, and oxidative cleavage of the diol formed [132, 133]. During the reaction, a substrate carbocation intermediate is formed, which is stabilized by cation-π interactions with the two aromatic residues in the substrate-binding cleft of BCMO1 [134]. Two oxygen atoms from two different sources are used, molecular oxygen and water; one retinaldehyde incorporates an oxygen atom from dioxygen, and the other retinaldehyde receives an oxygen from water [132]."

Spoiler

View attachment 17936​

"The observation of enhanced Bcmo1 expression in Caco-2 cells by triiodothyronine (T3), which is inhibited by actinomycin D, led Yamaguchi and Suruga [160] to the conclusion that the expression of the Bcmo1 gene might be regulated by T3 at the transcriptional level. However, these researchers were unable to make a clear assessment of whether the observed upregulation was directly a result of thyroid hormone receptor (TR) binding to thyroid hormone response elements (TREs) or due to enhanced PPAR-g transcriptional activity induced by T3 treatment of human intestinal cells. Nevertheless, these findings suggest that T3 might contribute to regulating b-carotene conversion to retinoid in the human small intestine [160]. Similar transcriptional dynamics were observed in experiments performed on rats [161] . Studying the influence of alcohol administration, which results in the decrease of hepatic retinoid levels, these investigators detected increased mRNA levels of Bcmo1, Bcmo2, Ppar-g, Ppar-a, and Tr-b, and the corresponding increases in the protein levels of BCMO2, PPAR-g, and PPAR-a. These findings support the idea that BCMO1 is transcriptionally regulated by PPAR-g in a process that may involve TR-b."

"Flavonoids such as luteolin, quercetin, and rhamnetin [made-up], which have a catechol structure in their B-ring, are remarkably efficient at inhibiting BCMO1 activity in a noncompetitive manner [165, 166]. This may be important for BCMO1 in the intestine, where it may be exposed to these flavonoids."

"Interestingly, an additional potential function for BCMO1 has been proposed recently based on microarray analysis of cadmium-exposed Caenorhabditis elegans and Hepa 1–6 murine hepatoma cells. These studies suggest that Bcmo1 may act as an early cadmium-responsive gene that is highly inducible by cadmium."

"Products of autooxidation formed from free radical attack on carotenoids may be more toxic prooxidants than the original free radicals. As a cause of oxidative stress induction [116 (image)], carotenoid oxidation products may lead to oxidative damage of different cellular components [117, 192], resulting in high cytotoxicity [116, 193]."

- Enzymology of vertebrate carotenoid oxygenases


- Is carotenoid ornamentation linked to the inner mitochondria membrane potential? A hypothesis for the maintenance of signal honesty (relating it to ubiquinone)

- Are aposematic signals honest? A review (on relialbiatwilaty of cues; there's the silly move of invoking this fancy term--that's more erudite than 'erudite' itself--in arguing that pigments are trustworthy when it comes to alarming predators when they should stay away, making strawberries, raspberries, cranberries, cherries, grapes, possibly beetroots, apples, watermelons, and so on, threats)

Spoiler

View attachment 17937

- Biological roles of fungal carotenoids

Again, you've invoked numerous mechanistic studies, none of which seem to argue or prove that Vitamin A is toxic. You seem to be abiding by the old adage...

"If you can't dazzle them with brilliance, baffle them with bull****"

And still, no one has addressed my criticism of Generux's claim of being on a Vitamin A FREE diet.

 

[Orion]

And still, no one has addressed my criticism of Generux's claim of being on a Vitamin A FREE diet.

Vitamin A is ubiquitous in nature, it is a low VA diet. POWs from WWII were probably the closest anyone would get to VA free, living off white rice only for few years.

 

[mrchibbs]

Again, you've invoked numerous mechanistic studies, none of which seem to argue or prove that Vitamin A is toxic. You seem to be abiding by the old adage...

"If you can't dazzle them with brilliance, baffle them with bull****"

And still, no one has addressed my criticism of Generux's claim of being on a Vitamin A FREE diet.

I think your criticisms are fair.