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

[maillol]

Some notes on Cytochrome P450 enzymes


Exposure to cigarette smoke subjects tissues to increased reactive oxygen species, which can induce cytochrome P450 enzymes and result in the degradation of retinoic acid, the bioactive form of vitamin A.

Alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases, induces cytochrome P450 enzymes (particularly CYP2E1) that degrade retinol and retinoic acid, and alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues.
From Alcohol and Tobacco Smoke in Retinoid Metabolism and Signaling: Implications for Carcinogenesis

-----------------------------------------

CYP2E1 also degrades retinoic acid and retinol to polar metabolites. Metabolism of retinoic acid not only results in the loss of retinoic acid promoting carcinogenesis through an increase in cell proliferation and dedifferentiation but also in generation of polar metabolites with apoptotic properties.
From <The role of cytochrome P450 2E1 in ethanol-mediated carcinogenesis - PubMed>

-----------------------------------------

Niacin (nicotinic acid) and its form – niacinamide (nicotinamide), collectively called as vitamin B3 inhibits CYP2E1
From <List of cytochrome P450 modulators - Wikipedia>

-----------------------------------------

It is concluded that in addition to CYP1A1 and CYP3A, CYP26 may be the main CYP enzyme responsible for the metabolism of all-trans-RA in enterocytes.
From https://pubmed.ncbi.nlm.nih.gov/11082432/


Inducers of CYP1A1

• Certain foods (e.g., broccoli, cauliflower, brussels sprouts, chargrilled meat)
• Insulin
• Methylcholanthrene
• Modafinil
• Nafcillin
• Omeprazole
• Phenytoin
• beta-Naphthoflavone
• Tobacco
From <List of cytochrome P450 modulators - Wikipedia>

That Wikipedia link above has a large list of inhibitors and inducers for the various P450 enzymes most of which seem to be involved in retinoid metabolism in some way. A noteworthy inhibitor is caffeine and as mentioned above, niacinamide. My thinking is that inducing these enzymes might help with eliminating vitamin A and it may also be a good idea to avoid inhibitors like niacinamide and grapefruit.

 

[InChristAlone]

Some notes on Cytochrome P450 enzymes


Exposure to cigarette smoke subjects tissues to increased reactive oxygen species, which can induce cytochrome P450 enzymes and result in the degradation of retinoic acid, the bioactive form of vitamin A.

Alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases, induces cytochrome P450 enzymes (particularly CYP2E1) that degrade retinol and retinoic acid, and alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues.
From Alcohol and Tobacco Smoke in Retinoid Metabolism and Signaling: Implications for Carcinogenesis

-----------------------------------------

CYP2E1 also degrades retinoic acid and retinol to polar metabolites. Metabolism of retinoic acid not only results in the loss of retinoic acid promoting carcinogenesis through an increase in cell proliferation and dedifferentiation but also in generation of polar metabolites with apoptotic properties.
From <The role of cytochrome P450 2E1 in ethanol-mediated carcinogenesis - PubMed>

-----------------------------------------

Niacin (nicotinic acid) and its form – niacinamide (nicotinamide), collectively called as vitamin B3 inhibits CYP2E1
From <List of cytochrome P450 modulators - Wikipedia>

-----------------------------------------

It is concluded that in addition to CYP1A1 and CYP3A, CYP26 may be the main CYP enzyme responsible for the metabolism of all-trans-RA in enterocytes.
From https://pubmed.ncbi.nlm.nih.gov/11082432/


Inducers of CYP1A1

• Certain foods (e.g., broccoli, cauliflower, brussels sprouts, chargrilled meat)
• Insulin
• Methylcholanthrene
• Modafinil
• Nafcillin
• Omeprazole
• Phenytoin
• beta-Naphthoflavone
• Tobacco
From <List of cytochrome P450 modulators - Wikipedia>

That Wikipedia link above has a large list of inhibitors and inducers for the various P450 enzymes most of which seem to be involved in retinoid metabolism in some way. A noteworthy inhibitor is caffeine and as mentioned above, niacinamide. My thinking is that inducing these enzymes might help with eliminating vitamin A and it may also be a good idea to avoid inhibitors like niacinamide and grapefruit.

Niacinamide is surprising. Do we have any evidence it makes vitamin A toxicity symptoms worse?

 

[maillol]

Niacinamide is surprising. Do we have any evidence it makes vitamin A toxicity symptoms worse?

Anecdotally it does make my symptoms worse. When I read that I was surprised too but also like ah!

 

[Dr. B]

Some notes on Cytochrome P450 enzymes


Exposure to cigarette smoke subjects tissues to increased reactive oxygen species, which can induce cytochrome P450 enzymes and result in the degradation of retinoic acid, the bioactive form of vitamin A.

Alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases, induces cytochrome P450 enzymes (particularly CYP2E1) that degrade retinol and retinoic acid, and alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues.
From Alcohol and Tobacco Smoke in Retinoid Metabolism and Signaling: Implications for Carcinogenesis

-----------------------------------------

CYP2E1 also degrades retinoic acid and retinol to polar metabolites. Metabolism of retinoic acid not only results in the loss of retinoic acid promoting carcinogenesis through an increase in cell proliferation and dedifferentiation but also in generation of polar metabolites with apoptotic properties.
From <The role of cytochrome P450 2E1 in ethanol-mediated carcinogenesis - PubMed>

-----------------------------------------

Niacin (nicotinic acid) and its form – niacinamide (nicotinamide), collectively called as vitamin B3 inhibits CYP2E1
From <List of cytochrome P450 modulators - Wikipedia>

-----------------------------------------

It is concluded that in addition to CYP1A1 and CYP3A, CYP26 may be the main CYP enzyme responsible for the metabolism of all-trans-RA in enterocytes.
From https://pubmed.ncbi.nlm.nih.gov/11082432/


Inducers of CYP1A1

• Certain foods (e.g., broccoli, cauliflower, brussels sprouts, chargrilled meat)
• Insulin
• Methylcholanthrene
• Modafinil
• Nafcillin
• Omeprazole
• Phenytoin
• beta-Naphthoflavone
• Tobacco
From <List of cytochrome P450 modulators - Wikipedia>

That Wikipedia link above has a large list of inhibitors and inducers for the various P450 enzymes most of which seem to be involved in retinoid metabolism in some way. A noteworthy inhibitor is caffeine and as mentioned above, niacinamide. My thinking is that inducing these enzymes might help with eliminating vitamin A and it may also be a good idea to avoid inhibitors like niacinamide and grapefruit.

doesnt caffeine increase liver function? also i dont see caffeine in your list?
it seems like any toxin will increase these enzymes though, i remember reading on selfhacked, estrogen also boosted these enzymes and diabetes also elevated them,

 

[maillol]

doesnt caffeine increase liver function? also i dont see caffeine in your list?
it seems like any toxin will increase these enzymes though, i remember reading on selfhacked, estrogen also boosted these enzymes and diabetes also elevated them,

Caffeine is in the list of inhibitors for CYP1A1. I'm not saying it's bad though, while it may inhibit CYP1A1 it also helps mobilise vitamin a from the liver. It increases cAMP which induces retinol binding protein. Caffeine also induces hepatic mPlrp2 and mClps expression which are involved in the hydrolysis of retinyl esters.

Yes you're right it seems many toxins induce P450 enzymes, the key would be focusing on inducers that are not toxic, or just avoiding inhibitors.

This might all be too orthorexic in reality but it's interesting to think about at least.

 

[Dr. B]

Caffeine is in the list of inhibitors for CYP1A1. I'm not saying it's bad though, while it may inhibit CYP1A1 it also helps mobilise vitamin a from the liver. It increases cAMP which induces retinol binding protein. Caffeine also induces hepatic mPlrp2 and mClps expression which are involved in the hydrolysis of retinyl esters.

Yes you're right it seems many toxins induce P450 enzymes, the key would be focusing on inducers that are not toxic, or just avoiding inhibitors.

This might all be too orthorexic in reality but it's interesting to think about at least.

black pepper is an inhibitor, used in supplements for that purpose, i dont remember it may be estrogenic too. ive avoided it for years, but didnt have it much before anyway. what else inhibits it? i think there were several Peaty things on the selfhacked list that apparently inhibited it?

so caffeine does help vitamin A toxicity?

 

[maillol]

black pepper is an inhibitor, used in supplements for that purpose, i dont remember it may be estrogenic too. ive avoided it for years, but didnt have it much before anyway. what else inhibits it? i think there were several Peaty things on the selfhacked list that apparently inhibited it?

so caffeine does help vitamin A toxicity?

That's good to know about pepper. I've avoided it for a long time too.

I think caffeine should speed up clearance of vitamin A but this also means it could make detox symptoms worse. I think this is why many people can't tolerate caffeine. My tolerance has improved so much over the last few months since going low A.

 

[youngsinatra]

Sorry if it already was mentioned, but this thread is so damn long:

What can we do besides eating a low vitamin A diet to help speed up the process?

I was thinking about if a „liver cleanse“ with caffeine, vitamin E and K2, taurine, choline or TUDCA could potentially help as most retinol is stored in the liver and many toxic effects of retinol are often times related to the liver such as fatty liver and elevated liver enzymes?

 

[redsun]

One thing I would like to add because I particularly noticed this from consuming 4oz of liver weekly for a few weeks. I couldnt quite figure it out until I could get out of the vitamin A induced brain fog. I was getting super dry eyes (my whole body was dry generally) my thoughts were not as deep, math was much more difficult (even things I have already done), I became somewhat antisocial, memory overall suffered, easily fatigue from exertion or working out. I was thinking dose dependent vitamin A decreased cortisol which was the reason it was giving me problems but really eventually I figured out that vitamin A dose-dependently lowers acetylcholine synthesis. I was in excess in vitamin A and I realized this basically causes autonomic dysfunction (perhaps sympathetic dominance since overall Ach is low), and the dry eyes and dry everything. Also explains memory, antisocial behavior, math errors, easy fatigue (Ach is needed for muscle contractions). Also indigestion, digestive problems (Ach necessary for digestive functions).

I still think low cortisol from vitamin A also is part of it, but clearly the main problem the vitamin A excess was going was inhibiting acetylcholine synthesis. Sympathetic activation (as well as epinephrine injection) also increases serum vitamin A as it increases mobilization from stores. So likely this is a way of speeding up the system (by inhibiting Ach synthesis) temporarily in times of need. But when this is due to vitamin A toxicity, the effect on Ach is more long-lasting.

It took me 3-4 weeks as I monitored symptoms for me to go to my prior state. This is still taking into account I was consuming plenty of choline promoting nutrients which the vitamin A left my system.

 

[aniciete]

One thing I would like to add because I particularly noticed this from consuming 4oz of liver weekly for a few weeks. I couldnt quite figure it out until I could get out of the vitamin A induced brain fog. I was getting super dry eyes (my whole body was dry generally) my thoughts were not as deep, math was much more difficult (even things I have already done), I became somewhat antisocial, memory overall suffered, easily fatigue from exertion or working out. I was thinking dose dependent vitamin A decreased cortisol which was the reason it was giving me problems but really eventually I figured out that vitamin A dose-dependently lowers acetylcholine synthesis. I was in excess in vitamin A and I realized this basically causes autonomic dysfunction (perhaps sympathetic dominance since overall Ach is low), and the dry eyes and dry everything. Also explains memory, antisocial behavior, math errors, easy fatigue (Ach is needed for muscle contractions). Also indigestion, digestive problems (Ach necessary for digestive functions).

I still think low cortisol from vitamin A also is part of it, but clearly the main problem the vitamin A excess was going was inhibiting acetylcholine synthesis. Sympathetic activation (as well as epinephrine injection) also increases serum vitamin A as it increases mobilization from stores. So likely this is a way of speeding up the system (by inhibiting Ach synthesis) temporarily in times of need. But when this is due to vitamin A toxicity, the effect on Ach is more long-lasting.

It took me 3-4 weeks as I monitored symptoms for me to go to my prior state. This is still taking into account I was consuming plenty of choline promoting nutrients which the vitamin A left my system.

Was it 4oz of beef liver? I have had really similar experiences with beef liver where I initially blamed the vitamin A, but it turns out it was the insanely high copper content. Ever since I switched to chicken liver my symptoms have vanished, so I’d assume it has to be the copper.

 

[redsun]

Was it 4oz of beef liver? I have had really similar experiences with beef liver where I initially blamed the vitamin A, but it turns out it was the insanely high copper content. Ever since I switched to chicken liver my symptoms have vanished, so I’d assume it has to be the copper.

It was adult beef liver which has the highest copper content but also it has 3x times more vitamin A than chicken liver. This may be why you are not getting much vitamin A build up from occasional chicken liver because even though it does have a lot its not an insane amount like adult beef liver. Copper does inhibit Ach synthesis and would not cause these problems. I have high histamine so I actually benefited from the copper in my case.

 

[Amazoniac]

- β-Carotene-Induced Alterations in Haemoglobin Affinity to O2

Spoiler

"The incorporation of carotenoids into model cell membranes and their impact on the physico-chemical properties of different membrane components have been extensively studied using various biophysical methods [8]. It was shown that carotenoids tend to adopt an extended conformation in lipid bilayers. Some of them were shown to increase the rigidity and stability of membranes and reduce their permeability to ions and oxygen [9,10]. Therefore, we have directed our interests towards exploring the effects of carotenoids on red blood cells (RBCs). The unique membrane skeleton of RBCs ensures the durability and flexibility of these cells, crucial for their proper functioning. Reversible deformation of RBCs is especially important during microcirculation [11]. Any changes in the properties of the membrane skeleton may affect the functioning of RBCs. Under uncontrolled conditions, they may lead to pronounced modifications of cell morphology that further result in the occurrence of undesirable clinical symptoms [12,13]. RBCs consist mainly of haemoglobin (Hb), which is found in the cytoplasm but can largely interact with proteins of the membrane skeleton, especially in its deoxidised form [14,15,16]. Haemoglobin is an α2β2 heterotetramer with embedded heme moieties. Its main functions (transport of O2 and CO2, buffering of H+ ions, NO metabolism) are already well-established. It is an allosteric protein: binding of one O2 to one heme-iron (HFe) increases the O2 affinity within the remaining groups. There are many allosteric modulators that affect the Hb-O2 binding equilibrium. Apart from well-known pH, pCO2 and 2,3-diphosphoglycerate, signaling molecules of a different type or natural and synthetic compounds may also induce its shift [17]. Furthermore, the interaction of Hb with the cytoplasmic domain bands 3 of the membrane of RBCs was found to influence the Hb-O2 affinity [14]."

"The above findings prompt us to explore the effect of β-Crt on the stability and functioning of RBCs, with emphasis on the possible changes of the physiological forms of Hb, its structure and molecular properties that may modify Hb-O2 affinity."

"The increase in the mean diameter of RBCs is already observed at a concentration of 25 μmol/L β-Crt, and the parameter d reaches its maximum at 50 μmol/L (it is about 15% larger in the case of treated RBCs when compared to control samples). RBCs incubated in the presence of a higher β-Crt concentration (100 μmol/L) are smaller than the control cells; however, an increase in their size is observed again in the presence of 500 μmol/L β-Crt (Figure 1a). It should be noted that the latter effect is associated with a significant elongation of RBCs. In this case, the longitudinal to lateral ratio is by about 20% larger than that estimated for the control samples (Figure 1b). The elongation of RBCs begins already at 50 μmol/L β-Crt."

"The above-described morphological alterations clearly indicate that β-Crt affects the membrane skeleton of RBCs. β-Carotene, as a non-polar compound, can easily incorporate into a cell membrane influencing its thickness, rigidity and inter-leaflet interactions [8,28]. It can freely rotate within the membrane and even flip around the membrane midplane, as was recently shown by molecular dynamics studies [28]. However, the mobility of β-Crt decreases with its increasing concentration. The motility of β-Crt has a noticeable effect on both types of membrane components: lipids and proteins. Therefore, its incorporation into the lipid bilayer of RBCs may influence the organisation and properties of the whole membrane skeleton. Our data is in line with recent results showing that at low β-Crt concentrations (up to 5 mol%), its motility can lead to local distortions in the lipid orientation and results in a less rigid membrane structure, making it more susceptible to deformations [28]."

"The presence of β-Crt, apart from the perturbation of the physical and chemical properties of the protein-lipid bilayers, results in an alteration in the functioning of ion channels, as observed by the reduced resistance of RBCs against haemolysis. However, a further increase of β-Crt concentration could result in its aggregation, as its elevated concentrations are known to make the membrane thicker and more rigid [28,29] and, as a consequence, less permeable to ions."

"At β-Crt concentrations >50 μmol/L, its enhanced interactions with the internal membrane structure are clearly seen (Figure 2). As previously mentioned, they are responsible for a serious rearrangement/disruption of the membrane skeleton network. Similar changes of the shape of RBCs were observed for hypertensive erythrocytes [13], as well as other pathological conditions [30,31]."

"[..]β-Crt may alter a highly specific interaction of Hb with the membrane skeleton protein(s). So far, it was shown that the interaction between DeoxyHb and band 3 protein is O2-dependent, and the cytoplasmic domain of band 3 (cdb3) was proved to be responsible for the shift of the ODC toward higher O2 partial pressures [15,16]. Here, under physiological conditions, decreasing the Hb-O2 affinity in β-Crt treated RBCs should increase the supply of O2 to resting and exercising tissues (Figure 5). The greatest and least effects were observed for RBCs100 and RBCs500, respectively. In the latter case, a new phenomenon is present, namely an increased Hb-O2 affinity at very low oxygen partial pressures in comparison to the control sample (Figure 3d, Figure 4 and Figure 5). It is worth noting that this phenomenon is accompanied by the most pronounced change in the shape of RBCs500 and decreased permeability of their membrane for Na+ ions (Figure 1 and Figure 2b)."

"In view of the above findings, β-Crt may turn out to act as a positive agent in the modulation of interactions between Hb and O2, facilitating adaptation to hypoxemia. On the other hand, its pro-oxidant potential should be kept in mind. The observed changes in Hb-O2 affinity upon β-Crt action may lead to local changes in the oxygen level. Enhanced delivery of oxygen to resting and/or exercising tissues may result in oxidative stress and formation of reactive derivatives. Although β-Crt is known to act as an efficient antioxidant in biological systems, there are some reports on its disadvantages, e.g., a carcinogenic response as a result of the elevated β-Crt presence, that were associated with the formation of β-Crt metabolites (its short-chain and long-chain cleavage products) [39,40]. In our case, the structural modification of β-Crt upon increased oxygen levels cannot be excluded. Hence, a formation of its oxidative breakdown products of pro-oxidant activity may take place that could further affect the morphology, stability and functionality of RBCs."

"The concentration of β-Crt used in our experiments (25–500 μmol/L) is about two orders of magnitude higher than the level usually detected in plasma (0.21–0.68 μmol/L) [23], which correspond to the average intake of β-Crt of 1–5 mg/day (or up to 10 mg/day depending on seasonal and regional variations) [41]. β-Carotene is delivered in form of food or supplements; however, no upper level of its intake has been established [41]. There are many reports of the administration of high doses of β-Crt (≥30 mg/day) for a long time which did not cause side effects in healthy people, although this resulted in its increased plasma concentration. The mean plasma concentration of β-Crt was more than 3 times higher compared to the control group, even after a short (9 days) β-Crt enriched diet (~40 mg/day) [42]. Moreover, in vivo studies showed that oral administration of an increased amount of β-Crt (580 mg/day for one week) resulted in an about 36-fold (~13 μmol/L) and a 7-fold increase in its concentration in plasma and RBCs, respectively [43]. Hence, the lower concentrations of β-Crt employed in our experiments can be reached in vivo by its high dietary intake such as via supplements."

Maybe chronic exposure to lower concentrations when turnover rate is decreased can lead to accumulation to disturbing levels.​

"The experiments were performed on material taken from healthy donors."

 

[Amazoniac]

- Severe pantothenic acid deficiency induces alterations in the intestinal mucosal proteome of starter Pekin ducks (@TheSir)

Spoiler

"Pantothenic acid is a precursor of two coenzymes, coenzyme A (CoA) and acyl-carrier-protein. The coenzymes of this vitamin participate in various metabolic reactions, such as glucose, fatty acids and amino acids entering into energy-yielding tricarboxylic acid (TCA) cycle, fatty acid oxidation and synthesis, cholesterol synthesis, acetylcholine synthesis, and heme synthesis etc. [1, 2]. Its importance is highlighted by the adverse effects of pantothenic acid deficiency (PAD) in mammals such as rats, cats, and pigs, including growth depression, skin lesions, diarrhea, loss of hair [2,3,4,5,6]. Also in poultry studies, PAD results in growth retardation, poor feathering, dermatosis, and high mortality in chicks, turkeys, geese, and ducks [7,8,9,10,11,12,13]. It has been demonstrated extensively that pantothenic acid can keep the structure of intestine integrity and maintain the intestinal function of animals [3, 14,15,16]. Intestinal hypofunction was shown to be a major consequence of PAD in rats, dogs, cats, chicks, and fish, such as intestinal ulceration, diarrhea, and colitis [4, 5, 17,18,19,20,21]. Rats deficient in pantothenic acid exhibit duodenitis and duodenal ulcers [18], as well as duodenal changes including eventual atrophy of crypts, diminution in size of villi [16]. In addition, previous studies in fish showed that PAD decreased intestinal digestive and absorptive capacities by reducing the activities of both intestinal brush border enzymes and digestive enzymes [14, 21]."

"In addition, pantothenic acid can protect cell membrane against peroxidative damage by increasing glutathione content [22,23,24]. Previous studies have shown that dietary PAD could lead to oxidative stress in geese [9] and fish [21]. It is proposed that oxidative stress induced by PAD leads to intestinal injury and hypofunction. So far, the detailed mechanisms of growth depression and intestinal hypofunction due to PAD are still unclear. In order to understand the underlying mechanisms, we established a PAD duck model, identified an overview of underlying processes and the extend of alterations of intestinal mucosa using a proteomic approach."

"A total of 22,973 peptide belonging to 3345 proteins were identified in the duodenum mucosa of two groups. Comparisons of the relative abundance of proteins from mucosa of PAD ducks with those of CON ducks showed that a total of 421 proteins showed a fold change (FC) > 1.5, of which 198 proteins were up-regulated and 223 proteins were down-regulated. The complete list of proteins altered by PAD is presented in Additional file 1."

"Based on the pathway analysis by Kyoto Encyclopedia of Genes and Genomes (KEGG), the significantly affected pathways were glycolysis and gluconeogenesis, amino acid metabolism, cori cycle, fatty acid beta oxidation, striated muscle contraction, TCA cycle, trans-sulfuration pathway, PPAR signaling pathway, cytoplasmic ribosomal proteins, vitamin A and carotenoid metabolism, oxidative stress, regulation of actin cytoskeleton, glutathione metabolism, and oxidative phosphorylation (Fig. 2)."

- Carotenoids and DNA damage

Carotenoids are among the best known antioxidant phytochemicals, and are widely believed to contribute to the health-promoting properties of fruits and vegetables. Investigations of the effects of carotenoids have been carried out at different levels: in cultured cells, in experimental animals, and in humans. Studying reports from the last 5 years, we find a clear distinction between effects of vitamin A and pro-vitamin A carotenoids (the carotenes and β-cryptoxanthin), and effects of non-vitamin A carotenoids (lycopene, lutein, astaxanthin and zeaxanthin). Whereas the latter group are almost invariably reported to protect against DNA damage, whether endogenous or induced by exogenous agents, the provitamin A carotenoids show a more varied spectrum of effects, sometimes protecting and sometimes enhancing DNA damage. The tendency to exacerbate damage is seen mainly at high concentrations, and might be accounted for by pro-oxidant actions of these carotenoids.

- The shifting perception on antioxidants: The case of vitamin E and β-carotene

"We have evaluated this dilemma by examining the presumed health effects of two individual antioxidants with opposite images i.e. the “poisonous” β-carotene and the “wholesome” vitamin E and focused on one aspect, namely their role in inducing BPDE-DNA adducts." ​

 

[Quelsatron]

I found out my serum retinol is 1.7 µl, on a test I took during july but forgot to check out. The reference range goes up to 3.3 µl, so I probably don't have vitamin A poisoning and my problems from liver are probably due to copper, I guess. Makes more sense given the histamine connection (thanks redsun!).

 

[Orion]

I found out my serum retinol is 1.7 µl, on a test I took during july but forgot to check out. The reference range goes up to 3.3 µl, so I probably don't have vitamin A poisoning and my problems from liver are probably due to copper, I guess. Makes more sense given the histamine connection (thanks redsun!).

1.7 to 3.3 is 48 to 93 µg/dL which is quite high. 3.3 as an upper range is probably extreme toxicity.

 

[Quelsatron]

1.7 to 3.3 is 48 to 93 µg/dL which is quite high. 3.3 as an upper range is probably extreme toxicity.

What are you basing that on? I'm sure it's a normal level for young males, is there some sort of different mechanism for recovering A-victims I've missed?

 

[Dr. B]

Sorry if it already was mentioned, but this thread is so damn long:

What can we do besides eating a low vitamin A diet to help speed up the process?

I was thinking about if a „liver cleanse“ with caffeine, vitamin E and K2, taurine, choline or TUDCA could potentially help as most retinol is stored in the liver and many toxic effects of retinol are often times related to the liver such as fatty liver and elevated liver enzymes?

choline supplements used daily, seem to drastically make skin more oily, and cause acne
i dont know if taurine will speed up the liver cleansing or help it, it slows digestion down dose dependently
i wonder how thiamnie would help things

One thing I would like to add because I particularly noticed this from consuming 4oz of liver weekly for a few weeks. I couldnt quite figure it out until I could get out of the vitamin A induced brain fog. I was getting super dry eyes (my whole body was dry generally) my thoughts were not as deep, math was much more difficult (even things I have already done), I became somewhat antisocial, memory overall suffered, easily fatigue from exertion or working out. I was thinking dose dependent vitamin A decreased cortisol which was the reason it was giving me problems but really eventually I figured out that vitamin A dose-dependently lowers acetylcholine synthesis. I was in excess in vitamin A and I realized this basically causes autonomic dysfunction (perhaps sympathetic dominance since overall Ach is low), and the dry eyes and dry everything. Also explains memory, antisocial behavior, math errors, easy fatigue (Ach is needed for muscle contractions). Also indigestion, digestive problems (Ach necessary for digestive functions).

I still think low cortisol from vitamin A also is part of it, but clearly the main problem the vitamin A excess was going was inhibiting acetylcholine synthesis. Sympathetic activation (as well as epinephrine injection) also increases serum vitamin A as it increases mobilization from stores. So likely this is a way of speeding up the system (by inhibiting Ach synthesis) temporarily in times of need. But when this is due to vitamin A toxicity, the effect on Ach is more long-lasting.

It took me 3-4 weeks as I monitored symptoms for me to go to my prior state. This is still taking into account I was consuming plenty of choline promoting nutrients which the vitamin A left my system.

what else boosts acetylcholine, and what else is involved in lubricating the saliva glands and tear glands/eyes? like sjogrens disease for instance, i dont know if acetylcholine helps it have you looked into acetylcholine as it relates to dry eyes/dry mouth like in sjogrens

wouldnt cortisol increase eye dryness, so lowering it should help? it could be the copper and pro methylation nutrients in the liver, strongly inhibiting histamine ?

would megadosing thiamine hcl, due to its acetylcholine boosting effects, be more effective on a high vitamin A diet.
how else can we increase acetylcholine, other than consuming choline as a supplement or choline rich foods?

 

[youngsinatra]

Vitamin A and Its Derivatives Induce Hepatic Glycine N-Methyltransferase and Hypomethylation of DNA in Rats

„Regulation of S-adenosylmethionine (SAM) and the SAM/S-adenosylhomocysteine (SAH) ratio by the key cytosolic enzyme glycine N-methyltransferase (GNMT) is essential in optimizing methyl group supply and subsequent functioning of methyltransferase enzymes. Therefore, inappropriate activation of GNMT may lead to the loss of methyl groups vital for many SAM-dependent transmethylation reactions. Previously, we demonstrated that the retinoid derivatives 13-cis- (CRA) and all-trans-retinoic acid (ATRA) mediated both the activity of GNMT and its abundance. The present study was conducted to determine whether vitamin A had a similar ability to up-regulate GNMT and to assess the biological importance of GNMT modulation by examining both the transmethylation and transsulfuration pathways after retinoid treatment. Rats were fed a control (10% casein + 0.3% l-methionine) diet and orally given retinyl palmitate (RP), CRA, ATRA or vehicle daily for 10 d. RP, CRA and ATRA elevated hepatic GNMT activity 32, 74 and 124%, respectively, compared with the control group. Moreover, the retinoid-mediated changes in GNMT activity were reflected in GNMT abundance (38, 89 and 107% increases for RP-, CRA-, and ATRA-treated rats, respectively). In addition, hepatic DNA, a substrate for SAM-dependent transmethylation, was hypomethylated (∼100%) after ATRA treatment compared with the control group. In contrast, the transsulfuration product glutathione was unaffected by retinoid treatment. These results provide evidence of the following: 1) vitamin A, like its retinoic acid derivatives, can induce enzymatically active GNMT; and 2) inappropriate induction of GNMT can lead to a biologically important loss of methyl groups and the subsequent impairment of essential transmethylation processes.“

Maybe a mechanism by which retinol causes fatty liver by depletion of methyl groups, as it is widely acknowledged that methyl donors (methionine, choline, betaine) help with fatty liver.

So supporting the methylation cycle with adequate B2, B6, B9, B12, creatine, choline/TMG and glycine as a methyl buffer may help?

 

[maillol]

Vitamin A and Its Derivatives Induce Hepatic Glycine N-Methyltransferase and Hypomethylation of DNA in Rats

„Regulation of S-adenosylmethionine (SAM) and the SAM/S-adenosylhomocysteine (SAH) ratio by the key cytosolic enzyme glycine N-methyltransferase (GNMT) is essential in optimizing methyl group supply and subsequent functioning of methyltransferase enzymes. Therefore, inappropriate activation of GNMT may lead to the loss of methyl groups vital for many SAM-dependent transmethylation reactions. Previously, we demonstrated that the retinoid derivatives 13-cis- (CRA) and all-trans-retinoic acid (ATRA) mediated both the activity of GNMT and its abundance. The present study was conducted to determine whether vitamin A had a similar ability to up-regulate GNMT and to assess the biological importance of GNMT modulation by examining both the transmethylation and transsulfuration pathways after retinoid treatment. Rats were fed a control (10% casein + 0.3% l-methionine) diet and orally given retinyl palmitate (RP), CRA, ATRA or vehicle daily for 10 d. RP, CRA and ATRA elevated hepatic GNMT activity 32, 74 and 124%, respectively, compared with the control group. Moreover, the retinoid-mediated changes in GNMT activity were reflected in GNMT abundance (38, 89 and 107% increases for RP-, CRA-, and ATRA-treated rats, respectively). In addition, hepatic DNA, a substrate for SAM-dependent transmethylation, was hypomethylated (∼100%) after ATRA treatment compared with the control group. In contrast, the transsulfuration product glutathione was unaffected by retinoid treatment. These results provide evidence of the following: 1) vitamin A, like its retinoic acid derivatives, can induce enzymatically active GNMT; and 2) inappropriate induction of GNMT can lead to a biologically important loss of methyl groups and the subsequent impairment of essential transmethylation processes.“

Maybe a mechanism by which retinol causes fatty liver by depletion of methyl groups, as it is widely acknowledged that methyl donors (methionine, choline, betaine) help with fatty liver.

So supporting the methylation cycle with adequate B2, B6, B9, B12, creatine, choline/TMG and glycine as a methyl buffer may help?

Good find

 

[youngsinatra]

Vitamin A Toxicity: The Case Story Of Chris Masterjohn (YouTube)