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

[Amazoniac]

Well they not only survived but also seemed to grow almost normally (+104% growth vs +136% in controls), they also mention a separate experiment where

"a group of 25 weanling male rats of the Sprague-Dawley strain (ordered specifically for purposes of vitamin A assay so as to have low vitamin A reserves) were placed on the vitamin A deficient diet (A^ ; 80% of the animals have survived for 80 days and attained an average weight of 245 gm. No xerophthalmia or marked visible evidence of vitamin A deficiency is apparent in these surviving animals. Of 6 control animals on the same diet but receiving vitamin A, all have survived, and their average weight at 80 clays was 370 gm."

Sure, the cure with Vitamin C wasn't 100%, but nevertheless suggests that much of the disease state caused by VA depletion diets in rats is secondary to disturbed Vitamin C metabolism. This makes it even more difficult to extrapolate from rat studies about the need for VA in humans since we have totally different Vitamin C metabolism.

I didn't understand how you arrived on those figures.

There was the peculiar 25,000 IU/d cirrhosis case in which you used to back up the idea that if such a low dose was capable of complicating the condition to that extent, what could be going on with other people passing unnoticed? The same applies here. For example, if animals managed to develop normally (they didn't) and tissues weren't analyzed, we could suppose that the depletion had no impact at all for a lack of manifestation.

 

[Amazoniac]

I was going to suggest Raj's leafy green brodo as cooking liquid for rice -- run through coffee filter to retain contaminants or juice jar with tap to avoid floating layer -- but then it occurred to me that there's something keeping them in solution (orange or tangerine juice as examples). It might be the proteins, those that require digestion to access the toxins, perhaps functioning in a similar way to the proteids in our blood that keep them soluble for transporation.

- Hydrophilic Carotenoids: Recent Progress (they is synthetic)

 

[Amazoniac]

Well they not only survived but also seemed to grow almost normally (+104% growth vs +136% in controls)

Oh, got it. That's not fair because it ignores actual values, they were far from ideal weight and both groups started from the same place.

 

[Mito]

Where are the references to show A is absolutely required to make those hormones?

I’ll see if I can find any besides Ray Peat.

Retinoic Acid Stimulates 17β-Estradiol and Testosterone Synthesis in Rat Hippocampal Slice Cultures

Steroid hormone synthesis is stimulated by retinoid in peripheral steroidogenic organs. In mouse Leydig cells, retinoid stimulate steroidogenic acute regulatory protein (StAR) gene expression and promoter function as well as steroidogenesis (31). The level of the mRNA for P45017α is enhanced by all-trans-retinoic acid in the K9 mouse Leydig cell line (32). Gene expression of StAR, P45017α, and P450scc and production of testosterone and dehydroepiandrosterone are stimulated by all-trans- and/or 9-cis-retinoic acid in human ovarian thecal cells (33).

Retinoic acids induce neurosteroid biosynthesis in human glial GI-1 Cells via the induction of steroidogenic genes. - PubMed - NCBI

Abstract
The steroids synthesized in the central nervous system (CNS) are the neurosteroids. Since little information is currently available concerning the roles of the retinoic acids (RAs) during steroidogenesis in the CNS, we investigated the effects of RAs upon their synthesis in our current study. Specifically, we analyzed the effects of all-trans-retinoic acid (ATRA) upon the expression of neurosteroid biosynthesis genes in the human glial cell line GI-1, in which the major steroidogenic genes are expressed. Treatment with ATRA (10 muM) induced a 4.9-fold increase in the expression of the cytochrome P450scc (CYP11A1) gene, the product of which cleaves the cholesterol side chain, a rate-limiting step during steroidogenesis. ATRA also strongly induced the expression of steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) (an increase of 5- and 50-fold, respectively). A retinoic acid receptor (RAR)-specific agonist, TTNPB, was unable to mimic this induction whereas a retinoid X receptor (RXR)-specific agonist, methoprene acid, in addition to 9-cis-RA, could do so. These data indicate that ATRA is isomerized to 9-cis-RA in the culture medium, as reported previously, and that 9-cis-RA activates the RXR. In addition, ATRA also induced the de novo synthesis of neurosteroids such as pregnenolone and progesterone. These results suggest that ATRA might induce the de novo neurosteroid synthesis via the induction of steroidogenic genes in human glial cells. The multiple effects of vitamin A upon CNS functions might therefore be partly explained by the induction of neurosteroidogenesis by RAs, since neurosteroids have also been reported to have multiple effects in the CNS.

 

[InChristAlone]

Retinoic Acid Stimulates 17β-Estradiol and Testosterone Synthesis in Rat Hippocampal Slice Cultures

Steroid hormone synthesis is stimulated by retinoid in peripheral steroidogenic organs. In mouse Leydig cells, retinoid stimulate steroidogenic acute regulatory protein (StAR) gene expression and promoter function as well as steroidogenesis (31). The level of the mRNA for P45017α is enhanced by all-trans-retinoic acid in the K9 mouse Leydig cell line (32). Gene expression of StAR, P45017α, and P450scc and production of testosterone and dehydroepiandrosterone are stimulated by all-trans- and/or 9-cis-retinoic acid in human ovarian thecal cells (33).

Retinoic acids induce neurosteroid biosynthesis in human glial GI-1 Cells via the induction of steroidogenic genes. - PubMed - NCBI

Abstract
The steroids synthesized in the central nervous system (CNS) are the neurosteroids. Since little information is currently available concerning the roles of the retinoic acids (RAs) during steroidogenesis in the CNS, we investigated the effects of RAs upon their synthesis in our current study. Specifically, we analyzed the effects of all-trans-retinoic acid (ATRA) upon the expression of neurosteroid biosynthesis genes in the human glial cell line GI-1, in which the major steroidogenic genes are expressed. Treatment with ATRA (10 muM) induced a 4.9-fold increase in the expression of the cytochrome P450scc (CYP11A1) gene, the product of which cleaves the cholesterol side chain, a rate-limiting step during steroidogenesis. ATRA also strongly induced the expression of steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) (an increase of 5- and 50-fold, respectively). A retinoic acid receptor (RAR)-specific agonist, TTNPB, was unable to mimic this induction whereas a retinoid X receptor (RXR)-specific agonist, methoprene acid, in addition to 9-cis-RA, could do so. These data indicate that ATRA is isomerized to 9-cis-RA in the culture medium, as reported previously, and that 9-cis-RA activates the RXR. In addition, ATRA also induced the de novo synthesis of neurosteroids such as pregnenolone and progesterone. These results suggest that ATRA might induce the de novo neurosteroid synthesis via the induction of steroidogenic genes in human glial cells. The multiple effects of vitamin A upon CNS functions might therefore be partly explained by the induction of neurosteroidogenesis by RAs, since neurosteroids have also been reported to have multiple effects in the CNS.

"Our finding of ATRA-induced neurosteroid biosynthesis in glial cells will provide a clue to our understanding of the multiple effects of RAs on the functions of the CNS. Further experiments using isolated primary cultured glial cells should be performed to evaluate our hypothesis."
This is hardly factual proof that vitamin A is absolutely necessary for synthesis of progesterone. Plus it doesn't explain why those who embark on the low VA diet end up lowering their cholesterol. If your cholesterol is high you aren't converting to steroids very well. I don't necessarily think low cholesterol is a good sign though. My cholesterol went way up after doing the standard Peat diet. Last year I was at increased risk for heart disease. Will be checking again this fall to see if monitoring my VA will have any effect.

 

[Collden]

Oh, got it. That's not fair because it ignores actual values, they were far from ideal weight and both groups started from the same place.

You're right I missed that the first value in the body weight table was after they'd already been on the diet for 20 days.

 

[Amazoniac]

You're right I missed that the first value in the body weight table was after they'd already been on the diet for 20 days.

But it's indeed confusing not to post initial values.

Another way of considering is that the weight difference between groups increased as time went by at any given period that you compare. As an example, for day 40 and 80 after the start, the difference was -109 g (245-354) and -203 g (302-505); so antidote C wasn't preventing the problem, it was getting worse. The poisoned animals had tissue linusic acid levels (measured at about day 40 in the separate experiment) that were beyond acceptable without requiring supplemental antidote at all.

--
For some reason when you brew leaves, the water ends up darker than before. If there are carotenoids pigmenting it as speculated, it must little considering that it's relatively difficult to extract them this way. So it's worth trying to use these liquids in rice preparation. There are also various teas that don't require toxic ingredients and they can be great for such purpose as well.

 

[postman]

Retinoic Acid Stimulates 17β-Estradiol and Testosterone Synthesis in Rat Hippocampal Slice Cultures

Steroid hormone synthesis is stimulated by retinoid in peripheral steroidogenic organs. In mouse Leydig cells, retinoid stimulate steroidogenic acute regulatory protein (StAR) gene expression and promoter function as well as steroidogenesis (31). The level of the mRNA for P45017α is enhanced by all-trans-retinoic acid in the K9 mouse Leydig cell line (32). Gene expression of StAR, P45017α, and P450scc and production of testosterone and dehydroepiandrosterone are stimulated by all-trans- and/or 9-cis-retinoic acid in human ovarian thecal cells (33).

Retinoic acids induce neurosteroid biosynthesis in human glial GI-1 Cells via the induction of steroidogenic genes. - PubMed - NCBI

Abstract
The steroids synthesized in the central nervous system (CNS) are the neurosteroids. Since little information is currently available concerning the roles of the retinoic acids (RAs) during steroidogenesis in the CNS, we investigated the effects of RAs upon their synthesis in our current study. Specifically, we analyzed the effects of all-trans-retinoic acid (ATRA) upon the expression of neurosteroid biosynthesis genes in the human glial cell line GI-1, in which the major steroidogenic genes are expressed. Treatment with ATRA (10 muM) induced a 4.9-fold increase in the expression of the cytochrome P450scc (CYP11A1) gene, the product of which cleaves the cholesterol side chain, a rate-limiting step during steroidogenesis. ATRA also strongly induced the expression of steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) (an increase of 5- and 50-fold, respectively). A retinoic acid receptor (RAR)-specific agonist, TTNPB, was unable to mimic this induction whereas a retinoid X receptor (RXR)-specific agonist, methoprene acid, in addition to 9-cis-RA, could do so. These data indicate that ATRA is isomerized to 9-cis-RA in the culture medium, as reported previously, and that 9-cis-RA activates the RXR. In addition, ATRA also induced the de novo synthesis of neurosteroids such as pregnenolone and progesterone. These results suggest that ATRA might induce the de novo neurosteroid synthesis via the induction of steroidogenic genes in human glial cells. The multiple effects of vitamin A upon CNS functions might therefore be partly explained by the induction of neurosteroidogenesis by RAs, since neurosteroids have also been reported to have multiple effects in the CNS.

This shows that RA stimulated neurosteroid biosynthesis, not that it is required for it. That's a very big difference. And the second study shows that any kind of RXR agonist can stimulate neurosteroid biosynthesis, not just retinol or retinol derivatives.

 

[Amazoniac]

- Anti-Peat - Grant Genereux's Theory Of Vitamin A Toxicity
↳ The effect of vitamin A deficiency on the biosynthesis of steroid hormones in rats

"Rats of both sexes and of this Institute strain were made vitamin A-deficient according to the procedure of Malathi et al. (1963)."​

↳ Studies on metabolism of vitamin A. 1. The biological activity of vitamin A acid in rats

"Commercial casein, as supplied by Polson and Co. (Bombay), was refluxed for 12 hr. on a boiling-water bath with approximately 3 vol. of ethanol acidified with HCl to pH 4-5. The casein was filtered off while still hot and reextracted by refluxing with light petroleum (b.p. 40-60°) for 12 hr. The extracted casein was then filtered, left overnight in an oven at 90° and finally stored at room temperature until used."​

"Table 1 [] shows that at the mildly deficient stage the activities of all the three tissues against all the substrates were decreased by nearly half. That no other compound was formed during the conversion of pregnenolone into progesterone was ascertained by occasional thin-layer chromatography of the extracts of the reaction mixtures in various solvent systems. In no case could we detect any other compound except pregnenolone and progesterone. Moreover, the net amounts of pregnenolone plus progesterone recovered after the reactions always accounted for almost all of the pregnenolone added. Therefore the decreased synthesis of progesterone from pregnenolone shown here reflects the net effects of vitamin A deficiency on this particular reaction."​

@Ella @haidut @Mito

 

[Amazoniac]

Sometimes they report losses from boiling, but it's difficult to tell if it's from leaching or degradation to other products that weren't tested or couldn't be detect'd.

Here's an where they were after a single compound and it changed after processing:

- Effect of boiling and microwave cooking on some antioxidant compounds in highly consumed vegetables in Egypt

"The highest loss of b-carotene (80%) was detected when artichoke was boiled. In contrast, when microwaving artichoke, only 8.04% of b-carotene was lost. There was a significant difference in β-carotene concentration (p<0.05) between fresh vegetables and boiled vegetables. On the other hand, no statistically significant difference was detected in b-carotene between fresh vegetables and micro-waved vegetables. Both boiling and microwaving caused a substantial loss of b-carotene, which could be explained by the consequent leaching of molecules into water and their instability at the boiling temperatures of the boiling process (100° C). Some researchers have reported similar results of b-carotene loss from vegetables, including spinach, amaranth and fenugreek, during cooking procedures, such as boiling, stewing, frying, blanching and pressure cooking [32, 33]. In contrast, [25] found no lutein content in the water after boiling vegetables in it, suggesting that no carotenoids leached out water during the boiling of the vegetables."​

The procedure was different, but now one that covered more:

- Effects of Chinese domestic cooking methods on the carotenoid composition of vegetables in Taiwan

"Boiling, stir-frying and deep-frying are common and specific domestic cooking methods in Taiwan. As shown in Table 2, stir-frying for 1 min and deep-frying for 2 s resulted in a significant loss of TCC [Total Carotenoid Content] in all vegetables, while all vegetables except the sweet potato leaf boiled in water retained the majority of total carotenoids. As for sweet potato leaf, boiling resulted in a slight but significant decrease in TCC (p < 0.05). Among single carotenoids, boiling caused almost no significant effect on (all-E)-forms of lutein, zeaxanthin, and b-carotene (p > 0.05), while the other two cooking methods resulted in a significant decrease of their contents."​

Contaminated brodo:

Spoiler

 

[Mito]

Abstract
“Spermatogenesis in mammals is a very complex, highly organized process, regulated in part by testosterone and retinoic acid (RA). There is a significant amount known about how RA and testosterone signaling pathways independently regulate this process, but there is almost no information regarding whether these two signaling pathways directly interact and whether RA is critical for steroidogenic cell function. This study utilized a transgenic mouse line that expresses a dominant negative form of RA receptor  (RAR−DN) and the steroidogenic cell−specific Cre mouse line, Cyp17iCre, to generate male mice with steroidogenic cells unable to perform RA signaling. Testes of mutant mice displayed increased apoptosis of pachytene spermatocytes, increased number of macrophages in the interstitium, and missing advanced germ cells. Additionally, blocking RA signaling in Leydig cells resulted in increased permeability of the blood-testis barrier, decreased levels of the steroidogenic enzyme cytochrome P450 17a1, and decreased testosterone levels. Surprisingly, the epididymides of the mutant mice also displayed an abnormal phenotype. This study demonstrates that RA signaling is required in steroidogenic cells for their normal function and, thus, for male fertility.”

Discussion
“The main function of Leydig cells is to produce testosterone essential for the normal progression of spermatogenesis (O'Donnell, McLachlan et al. 1994; O'Donnell, McLachlan et al. 1996; De Gendt, Swinnen et al. 2004; De Gendt, Atanassova et al. 2005). Until this study, it was unclear whether RA and testosterone essential for normal spermatogenesis interact with each other. This study provides the first evidence to detail the importance of RA signaling in Leydig cells for their normal function and proper spermatogenesis. Inhibition of RA signaling activity within Leydig cells, via the expression of the RAR-DN, resulted in alterations of Leydig cell function causing spermatogenic errors, cell death, decreased levels of testosterone, and increased numbers of macrophages. In addition to the testicular phenotype, we also found that the expression of the RAR-DN in the steroidogenic cells caused an epididymal phenotype. This study demonstrated, for the first time, that RA signaling is important in steroidogenic cells for normal testosterone production and epididymal development.”

https://dev.biologists.org/content/develop/early/2018/06/09/dev.160465.full.pdf

 

[thomas200]

Here is an update on my progress - nearly month 8:

i'm still waking up in the middle of the night since about 2 months ago. It's starting to occur less often

I have TERRIBLE mood swings... 2 days ago I was filled with absolute rage, I didn't even feel like myself. Yesterday I felt the happiest i've been my whole life, and today I'm feeling down. I've never experienced mood swings like this ever and it scares me a little lol..

I went on a tropical vacation recently where it's really humid, and I noticed my dry knuckles fade completely. It's been 3 days since i returned and my dry knuckles seem to have vanished (knock on wood). It's been months since my knuckles have bled from being so dry, I don't think i'll be facing that problem anymore . They do tend to get red under sunlight though

VA toxicity turned me into an introvert, and it took me a few months to notice that one. I am interacting more with my friends and I feel myself going back to who I was and it's honestly the best feeling ever

 

[somuch4food]

Here is an update on my progress - nearly month 8:

i'm still waking up in the middle of the night since about 2 months ago. It's starting to occur less often

I have TERRIBLE mood swings... 2 days ago I was filled with absolute rage, I didn't even feel like myself. Yesterday I felt the happiest i've been my whole life, and today I'm feeling down. I've never experienced mood swings like this ever and it scares me a little lol..

Have you tried anything regarding those mood swings? Maybe more B vitamins, or some mineral would help. I do also have those mood swings when I eat too much colorful fruits and vegetables (carotenoids). I can imagine the dumping because of low intake would make it much more intense than with my higher intake. Dairy seems to be what calms me most. Lemonade and apple juice also seem to have some effects in leveling my moods.

I encourage you to try different food combinations to see if they help.

 

[Andy316]

Here is an update on my progress - nearly month 8:

i'm still waking up in the middle of the night since about 2 months ago. It's starting to occur less often

I have TERRIBLE mood swings... 2 days ago I was filled with absolute rage, I didn't even feel like myself. Yesterday I felt the happiest i've been my whole life, and today I'm feeling down. I've never experienced mood swings like this ever and it scares me a little lol..

I went on a tropical vacation recently where it's really humid, and I noticed my dry knuckles fade completely. It's been 3 days since i returned and my dry knuckles seem to have vanished (knock on wood). It's been months since my knuckles have bled from being so dry, I don't think i'll be facing that problem anymore . They do tend to get red under sunlight though

VA toxicity turned me into an introvert, and it took me a few months to notice that one. I am interacting more with my friends and I feel myself going back to who I was and it's honestly the best feeling ever

1.5 months into low VA diet and I can agree with the mood swings. What has really helped is "Sugarcane juice" which is very low VA and is a good liver detox. I remember when I had Hepatitis A (Jaundice) as a 8 year old with yellowish skin tone/eyes, the doctor at the time recommended Sugarcane juice which really helped with curing my Jaundice quickly and plus it tastes yumm.

 

[Collden]

Here is an update on my progress - nearly month 8:

i'm still waking up in the middle of the night since about 2 months ago. It's starting to occur less often

I have TERRIBLE mood swings... 2 days ago I was filled with absolute rage, I didn't even feel like myself. Yesterday I felt the happiest i've been my whole life, and today I'm feeling down. I've never experienced mood swings like this ever and it scares me a little lol..

I went on a tropical vacation recently where it's really humid, and I noticed my dry knuckles fade completely. It's been 3 days since i returned and my dry knuckles seem to have vanished (knock on wood). It's been months since my knuckles have bled from being so dry, I don't think i'll be facing that problem anymore . They do tend to get red under sunlight though

VA toxicity turned me into an introvert, and it took me a few months to notice that one. I am interacting more with my friends and I feel myself going back to who I was and it's honestly the best feeling ever

Wouldn't necessarily say mood swings are a bad thing if they are a result of increased overall emotional intensity. Flat moods and inability to feel strong emotions are a hallmark of poor metabolism.

 

[Andy316]

Is topical application of Vit A products (Creams, shampoos, hair oils) allowed in this program?

 

[Louise]

Is topical application of Vit A products (Creams, shampoos, hair oils) allowed in this program?

I don't think shampoos with it are a big deal but you shouldn't use products with it that would be kept on the skin allowing for maximum absorption of vitamin A.

 

[Orion]

I don't think shampoos with it are a big deal but you shouldn't use products with it that would be kept on the skin allowing for maximum absorption of vitamin A.

@Andy316 I agree with @Louise believe there have been some studies showing the transdermal uptake of VA is quite efficient, so probably best to avoid if testing low VA eating.

 

[Andy316]

@Andy316 I agree with @Louise believe there have been some studies showing the transdermal uptake of VA is quite efficient, so probably best to avoid if testing low VA eating.

Thanks @Orion and @Louise

 

[Amazoniac]

You'll find that some of these topics were already covered in this thread, but since there are extra details, they was included. It's better to read the article instead of these quotes. This for acute infections, but perhaps something still applies when it's chronic.

- Role of Fat-Soluble Vitamins A and D in the Pathogenesis of Influenza: a new perspective

"It has been proposed that (1) reduced exposure to sunlight and/or preexisting vitamin D deficiency simultaneously increase the accumulation and potential toxicity of endogenous retinoids, while the decreased vitamin D-to-vitamin A ratio triggers viral activation or increases susceptibility to novel strains of influenza virus; (2) increased but normal physiological concentrations of retinoid effectively work with vitamin D to inhibit influenza pathogenesis; and (3) higher background concentrations of vitamin A (i.e., very low vitamin D : A ratios), for example, associated with diseases and conditions affecting the liver, enhance viral replication and increase the likelihood of severe or lethal complications of the disease. It is possible and indeed likely that, on the vitamin A side, different retinoid receptor isotypes (RARs, RXRs) will prove to be involved in the outcomes of altered vitamin D : A ratios, either enhancing or inhibiting infection and viral replication, depending on the background level of retinoids in the body. For instance, one group of retinoid receptor isotypes may facilitate and exacerbate influenza viral infections, while another set may come into play to inhibit viral proliferation and infection.

In summary, it is proposed that lack of solar radiation and/or vitamin D deficiency increase the availability and potential toxicity of retinoids, and the latter interact with and induce viral activation at the genome level to trigger influenza. On this hypothesis, influenza viral pathogenesis involves both vitamin D deficiency and endogenous retinoid overexpression. In seasonal influenza, ever-present influenza viruses may be activated and disease symptoms triggered by declining vitamin D concentrations and worsened by retinoid accumulation and overexpression. In pandemic influenza, while the virulence of the strain of virus may account for disease epidemicity, the likelihood of particular individuals being infected may depend on the background nutritional status of vitamin A and D, whereby infectivity may be reduced by vitamin D supplementation but enhanced by vitamin A supplementation or excess. Retinoid receptor overexpression may thus contribute to the pathogenesis of influenza and related viral infections, causing an endogenous form of hypervitaminosis A that manifests itself in the symptoms of the disease."

Spoiler

"Solar radiation increases vitamin D levels, as noted above. On the other hand, vitamin A is sensitive to photooxidation and may be destroyed by it. Two forms of vitamin A are found in human skin: all-trans-retinol (A1) and 3-dehydroretinol (A2). Dermal retinol is derived partly from the adjacent subcutis, which contains 10–20 times more vitamin A than both skin and blood [83]. 3-Dehydroretinol occurs mainly in the epidermis and may be a metabolite of retinol [84]. Small amounts of retinoic acid are also found in human skin and represent a mixture of 13-cis/trans isomers of retinoic acid. In Caucasian human skin, levels of retinyl esters and retinol are 3.5 and 5.0 times higher, respectively, in the epidermis than in the dermis [85].

As an intrinsic modulator of proliferation and differentiation in human epidermis, vitamin A may be destroyed by ultraviolet radiation (UVR) impinging on the skin. The solar spectrum of UVR (290 to 400 nm) is commonly divided into three bands, from longer to shorter wavelength regions: UVA (320–400 nm), UVB (290–320 nm), and UVC (200–290 nm). UVB and UVA radiation are the principal wavelengths causing sunburn [86]. The absorption maxima of most retinoids range from 280 to over 400 nm [87]. From 35% to 50% of incident ultraviolet-A radiation (UVA) is transmitted through Caucasian epidermis [88] and absorbed directly by blood in the capillaries of the papillary dermis. UVA radiation produces histologic changes in skin at greater depths than the shorter UVB or UVC wavelengths [89]. Ultraviolet radiation has a biphasic effect on human blood vitamin A levels [90]: first, an increase, which peaks at 7 hours following irradiation, and then a fall 24–48 hours later. Tang et al. [85] investigated the effect of sunlight on retinyl esters and retinol in human skin, blood, and cultured keratinocytes. Sunlight irradiation led to a significant reduction in epidermal retinyl esters in Caucasian skin in both summer and winter, whereas epidermal and dermal retinol and dermal retinyl esters were affected to a lesser extent. When serum from volunteers who had taken a large dose of retinyl palmitate to elevate serum retinyl esters was exposed to sunlight, the serum retinyl esters disappeared after 10 minutes of exposure. Andersson et al. [91] studied endogenous retinoid concentrations and metabolism in cultured human keratinocytes and melanocytes exposed to UVR. Before UVR the retinoid content was similar in keratinocytes and melanocytes. In both cell types, UVR (i.e., UVA 360 mJ/cm2 plus UVB 140 mJ/cm2) instantaneously reduced the concentration of retinol by about 50% and that of 3,4-didehydroretinol by about 20%. The uptake of retinol was threefold higher and that of retinoic acid was tenfold higher in the melanocytes, and in both types of irradiated cells the accumulation of the biologically most active metabolite, all-trans retinoic acid, was about 60% higher than in control cells. Retinoid concentrations returned to normal within 1-2 days after irradiation. The metabolism of retinoic acid was reduced, especially in irradiated keratinocytes, which may have contributed to the restoration of retinoid levels after UV exposure. These observations point to a complex pattern and sequence of changes in retinoid metabolism following exposure to solar radiation."


"[..]evidence suggests that in the event of major perturbations in either vitamin A or D, due to dietary or other factors, there is an inverse, mutually inhibitory relationship between them in that vitamins A and D counterbalance their potentially toxic individual effects [94]. For instance, while vitamin A can reduce the toxicity of vitamin D (e.g., [92, 95]), vitamin D can also interact inversely with vitamin A and reduce the toxicity of vitamin A. Although little is known about the effect of reduced sunlight exposure and/or deficient vitamin D levels on vitamin A metabolism, even small to moderate doses of vitamin D in chickens reduce liver vitamin A stores and lower the level of vitamin A in blood [96]. Exposure of chickens to UV light (which produces vitamin D) likewise reduces liver stores and blood levels of retinol [97]. In humans, concomitant supplementation with vitamin D greatly increases the dose of vitamin A required to cause toxicity; for instance, Myhre et al. [98] found that the median dose for inducing vitamin A toxicity was >2,300 IU/kg of body weight per day higher when vitamin D was added to the diet. For a hypothetical 75 kg person representing the median, vitamin D supplementation would have allowed an additional 175,000 IU vitamin A/day before toxicity symptoms were likely to be reported. In the Nurses’ Health Study, a positive association was found between retinol intake and fracture risk in that vitamin D intake increased as retinol intake increased, but at a lower rate. In a multivariate analysis controlling for many factors, vitamin D was found to be protective against retinol-associated risks of fracture [99]."


"With regard to the impact of vitamin A on vitamin D, in humans the amount of vitamin A in a single serving of liver inhibits the rise in serum calcium induced by vitamin D [101]. Retinoic acid can antagonize the action of vitamin D and its active metabolite 1,25-dihydroxycholecalciferol in rats [102]. A high intake of retinol also completely abolished the protective effect of vitamin D on distal colorectal adenoma, women in the highest quintile of vitamin D intake ingested about 10,000 IU/day of retinol, and there was a strong correlation overall between dietary intakes of vitamins A and D [103]."


"Vitamin A is affected by changes in temperature as well as light; both light and warm temperatures cause vitamin A to be catabolized. In one study, twin calves were fed 6 mg carotene daily per 100 lb body weight and subjected to high and low ambient temperatures. High temperatures increased liver vitamin A utilization; moreover, identical twin calves exposed to solar radiation for 38 days lost more hepatic vitamin A than their cotwins in the shade [106]. Thus, rising temperatures and greater sunlight in the summer months could catabolize tissue concentrations of vitamin A to such a degree that it would prevent influenza viruses from making use of it to replicate. Conversely, the seasonal increase in influenza during the winter months may occur partly from the fact that vitamin A remains available for the virus to replicate in cooler temperatures.

In summary, reduced solar radiation and cooler temperatures during the winter months may serve at once to reduce vitamin D reserves and to increase the accumulation and hence potential toxicity of vitamin A, that is, to lower the vitamin D : A ratio. Here it is proposed that the increased endogenous concentrations of vitamin A in turn interact with and activate the influenza virus, resulting in the signs and symptoms of infection via molecular mechanisms that are discussed[.] If this hypothesis is correct, not only reduced solar radiation and vitamin D deficiency but also vitamin A supplementation (and/or conditions associated with high preexisting retinoid concentrations) could increase susceptibility to influenza, especially in a situation of reduced sunlight exposure and/or vitamin D deficiency. At the same time—given the interaction between vitamins A and D—vitamin D supplementation may protect against influenza, partly by inhibiting the expression of vitamin A."


"Influenza infection primarily but not exclusively affects the respiratory system. Vitamin A and its active metabolites are likewise importantly involved in the growth and differentiation of mucosa-associated airway epithelia. Delivery of retinol via the bloodstream to target cells ensures a sufficient cellular supply. Vitamin A is stored in the target tissues as retinyl esters, which provide an additional source of the vitamin [107]. Retinoic acid, the major biologically active metabolite of retinol, plays an essential role in the regulation of airway epithelial cell growth, differentiation, and gene expression. Levels of retinoid binding proteins, the RA receptors, and RA synthesizing enzymes all peak postnatally. Retinoic acid is also required throughout life for the maintenance of lung alveoli, and a deficiency leads to a loss of alveoli and to features of emphysema. Exogenous retinoic acid has been reported to induce alveolar regeneration in a rat model of experimental emphysema, and an inhibitor of retinoic acid synthesis, disulfiram, disrupts alveologenesis [108]."

"In an unusual case report, the symptoms of influenza A infection were described as being perfectly mimicked by the retinoic acid syndrome [116]." "Headache, a common symptom of influenza [117], is also a major feature of retinoid toxicity [118]. Conjunctivitis and photophobia are also common during acute seasonal influenza infection, especially in avian influenza A infections in humans [119]. An oculorespiratory syndrome (ORS) consisting of red eyes, photophobia, blurred vision, palpebral edema, ocular pain and itching, and conjunctival secretions is reported after influenza vaccination [120]. A similar pattern of ocular side effects has been described in diet-induced hypervitaminosis A and secondary to isotretinoin use. In a review of 1,741 spontaneous case reports, as well as data from the Drug Safety Section of Roche Pharmaceuticals and the world literature, adverse ocular reactions classified as “certain” to have been associated with isotretinoin use included photophobia, abnormal meibomian gland secretion, blepharoconjunctivitis, corneal opacities, decreased dark adaptation, decreased tolerance to contact lens, decreased vision, increased tear osmolarity, keratitis, meibomian gland atrophy, myopia, ocular discomfort, and ocular sicca [121]. Similarities between the features of hypervitaminosis A and influenza infection are shown in Table 1."


"It has been recognized for decades that vitamin A deficiency is associated with increased susceptibility to most infections and with defects in the innate and adaptive immune systems [67]. The traditional view of vitamin A as an “anti-infective” vitamin was based partly on earlier studies in which vitamin A—in cod liver oil (CLO)—was successful in preventing infection [122]. Since earlier preparations of CLO contained higher amounts of vitamin D in proportion to vitamin A than do currently available preparations, possibly due to modern deodorization procedures, which remove vitamin D, it has been suggested by Cannell et al. [34, 35] that the anti-infective properties of CLO were partly or wholly due to vitamin D."


"Consistent with the role of retinoic acid in cell growth and differentiation, viral growth is also regulated in part by vitamin A [129]. A number of virus infections are known to be influenced in complex ways by retinoids. For instance, when different cell lines are infected with human cytomegalovirus (hCMV), exposure of the cells to retinoic acid (RA) enhances viral gene expression and susceptibility to infection [129]. RA also reactivates CMV expression in latently infected glioblastoma cells in tissue culture [130]. Reactivation of latent virus is believed to result from a signal transduction event that induces immediate-early (IE) gene transcription, a crucial viral control element. Ghazal et al. [131] have shown that the major IE promoter of hCMV is activated by physiological levels of RA in human embryonal carcinoma cells (i.e., functions as a retinoic acid response element or RARE) and is a specific target site for the direct interaction of nuclear receptor proteins for RA. These findings suggest that RA is a potential modulator of hCMV pathogenesis."

"Murine CMV (mCMV) is also susceptible to regulation by natural and synthetic retinoids at different levels. In tissue culture cells, the major IE enhancer can be activated by RA via multiple RA-responsive elements (RAREs) that bind RXR-RAR heterodimers. Viral growth was dramatically increased following RA treatment of infected tissue culture cells. RAR activation was required to mediate the response of mCMV to RA and selectively promoted viral growth; moreover, the stimulatory effects of RA on enhancer activity and viral growth were prevented by treatment with an RAR-specific antagonist. Oral administration of RA to infected mice worsened an acute infection by mCMV, whereas an RAR-antagonist, also administered orally, protected against the adverse effects of RA in mCMV infection [132]."

"[..]authors suggest that production of RA during EBV infection may enhance viral replication by promoting keratinocyte differentiation."


"Retinoic acid has a concentration-dependent effect in promoting Th17 responses: low doses (1 nM) stimulate Th17 responses whereas higher doses (10 nM) suppress both Th17 and Th1 responses [150, 151]." "Th1 adaptive immunity is an important response against intracellular microbes such as viruses, and Th17 cells participate in host defense reactions as well as in tissue inflammation in several autoimmune diseases, allergic diseases, and asthma [155]."


"Infection of human airway epithelial cells with human rhinovirus, both in vitro and in vivo, increases the expression of inducible nitric oxide (NO) synthase, which correlates with increased levels of NO in exhaled air. The common cold is triggered by a variety of viral pathogens, mostly rhinoviruses; complications include sinusitis, otitis media, and exacerbations of asthma and chronic obstructive lung disease. NO inhibits human rhinovirus-induced epithelial expression of several proinflammatory cytokines; it inhibits viral replication in epithelial cells in vitro and modulates several signal transduction pathways associated with cytokine generation; it is also involved in the nitrosylation of viral proteases and interacts with the immune system. Increased NO generation during rhinovirus infections is associated with fewer symptoms, more rapid improvement in symptoms, and more rapid viral clearance [176]."

"Observations on the roles of apoptosis and nitric oxide (NO) in colds and inuenza are relevant to the hypothesis that the severity of inuenza infection is associated with increased retinoic acid concentrations. Retinoids are inversely related to and suppress cytokine-induced production of NO, which is antiapoptotic, whereas retinoic acid is proapoptotic [178]. Nitric oxide is a potent vasodilator, generated enzymatically from L-arginine by the action of nitric oxide synthase (NOS) [179]. All-trans-RA blocks the release of tumor necrosis factor from peritoneal macrophages stimulated with endotoxin and interferon-gamma and inhibits NO production in these cells [180]."


"Respiratory infections in humans, including influenza, are often accompanied by mild hepatitis, although the mechanisms are not well understood. In their study of patients who were hospitalized with severe nvH1N1 infection, Bermejo-Martin et al. [154] found that, in addition to the symptoms of fever, cough, headache, tiredness, myalgia, and dyspnea, lactate dehydrogenase and transaminases were raised fourfold above those of hospitalized but noncritical illness controls, providing evidence of necrotic damage in the liver. Polakos et al. [111] infected 15 subjects intranasally with influenza A (H1N1), and 4/15 developed elevated serum transaminases (>3 times the upper limit in 2 subjects), suggesting clinically significant hepatitis. The rise in liver enzymes occurred after the decline in fever, implying that liver involvement was not caused by the initial viral replication and activation of the innate immune system. Hepatocytes were found to be damaged by viral specific CD8+ T cells generated in the lungs, a condition Polakos et al. described as “collateral damage”, since there was no evidence of influenza viral antigen in the liver."

"The model proposed here aims to explain the mechanism of inuenza A-associated liver dysfunction and its role in increasing the severity of infection. It is consistent with the overall low vitamin D : A ratio hypothesis of severe inuenza and involves alterations in retinoid metabolism. It is suggested that influenza-induced liver involvement worsens the outcome of infection via the hepatic release of unbound retinyl esters and retinoic acids which are transported to and damage the lung as well as other organs, thereby contributing to the development of pneumonia, heart and kidney failure, and sepsis."


"(1) Viral-specific CD8+ T cells generated in response to influenza infection outside the liver trigger cell-mediated apoptotic hepatitis [111]. This process may occur through infection-induced activation of the retinoid cascade in the liver, leading to increased retinoic acid production and RAR activation and expression within the hepatic cell nuclei."

"[..]influenza-induced increased RAR activation inhibits the production and secretion of retinol binding-protein (RBP) via a process of feedback inhibition [185], thereby lowering serum retinol concentrations and simultaneously increasing the accumulation and expression of retinoids in the liver. These changes induce inflammation and tissue damage, consistent with the known role of excessive vitamin A in inducing liver damage [186] and apoptosis [187]. The suggested mechanism of tissue damage involves Kupffer cells which, in addition to being the source of macrophages in the liver, also play a critical role in hypervitaminosis A. Vitamin A activates Kupffer cells through INF-γ production by activated T lymphocytes [188], and activated Kupffer cells potentiate liver toxicity even with low levels of hepatotoxins such as alcohol [189]. Hence, the observation of Polakos et al. [111] that the severity of hepatitis in mice infected with influenza was reduced in the absence of Kupffer cells could be due to the fact that these cells play a critical role in the processes mediating vitamin A intoxication."

"During hepatic fibrosis, the normally quiescent vitamin A-storing stellate cells transform into myofibroblastic cells and lose their intracellular droplets of retinyl esters, the storage form of vitamin A. The loss of retinyl esters is associated with increased RA formation, which in turn facilitates TGF-beta-mediated liver fibrogenesis [194]. This phenotypic transformation induces potent proinflammatory and profibrogenic activities and is underpinned by changes in the expression of numerous genes [195]."

Damage or insult here came first.


"(2) Retinoid-induced Kupffer cell activation and hepatotoxicity, lead to a transient form of cholestatic liver dysfunction, a condition in which bile regurgitates into the circulation, raising the level of all biliary substances in the blood [192, 196].

In cholestasis, vitamin A metabolites and bile acids are refluxed from the liver and stored retinyl esters leak into the circulation from damaged hepatocytes. Metabolites of retinol, retinyl acetate, retinal, retinoic acid, retinol beta-glucuronide, retinotaurine, and other unidentified vitamin A compounds are excreted in the bile [79, 197] in proportion to the total liver stores of the vitamin [198]. A variety of infections and stressors are associated with transient declines in plasma retinol concentrations [199, 200], but plasma retinol concentrations tend to rebound when the inflammatory stimulus is removed [201].

The hypothesized net effect of transient cholestasis in influenza A infection is high circulating concentrations of retinoid metabolites and retinyl esters, with low or normal concentrations of retinol and RBP. In studies of infective hepatitis, the RBP-prealbumin complex and plasma vitamin A were decreased in association with reduced hepatic mobilization and very high liver levels of vitamin A, resulting in a mixed symptom pattern of hypo- and hypervitaminosis A [202]."


"(3) Retinoic acid and stored retinyl esters released into the circulation from damaged liver cells cause acute lung injury (ALI) via apoptosis and necrosis of lung tissue."

"A low vitamin D : A ratio has been postulated to increase the severity of influenza infection. The risk of severe illness may be further exacerbated by the effect of illness on the liver and its stored contents of vitamin A. On this model, activation of the retinoid cascade causes liver damage and the spillage of retinoic acid and unbound retinyl esters into the circulation."


"(4) The mechanisms of tissue damage following the release of retinoids from the liver in influenza infection also could be due to the hepatic release of the enzyme xanthine oxidase (XO), which affects vitamin A metabolism.

Mice infected intranasally with influenza virus have high levels of XO, TNF, and IL-6 in bronchoalveolar lavage within 3 d after infection, as well as high levels of XO in serum and lung tissue [208, 209]. In humans, XO plays an important role in the catabolism of purines and is normally found in the liver but is released into the blood during severe liver damage [210]. XO catalyzes the oxidation of hypoxanthine to xanthine and of xanthine to uric acid. XO can also catalyze the conversion of retinaldehyde to retinoic acid [211]. Hence, increased circulating XO may be associated with increased concentrations of retinoic acid."


"The increased risk of severe influenza on the part of individuals with diabetes and the obese may be related to liver dysfunction and alterations in retinoid metabolism, as suggested above. Aging is also associated with an increased risk of hospitalization and death from influenza-associated pneumonia, and people of age 65 and older account for >90% of influenza-related deaths [224]. Could aging be associated with increased susceptibility to severe influenza due to a progressive accumulation of retinoids with advancing age? Several observations support this hypothesis: serum levels of vitamin A increase in elderly populations [225, 226]; intracellular retinoids and retinoid-binding proteins are present in leucocytes (granulocytes and mononuclear cells) and increase quadratically with age; serum concentrations of retinoic acid increase in the elderly [227]; vitamin A absorption is also increased in elderly humans and animals [228, 229]."

--
- Anti-Peat - Grant Genereux's Theory Of Vitamin A Toxicity

"[..]many investigators have noted great reduction in the incidence of colds and respiratory infections through the use of fairly liberal quantities of cod liver oil. Holmes and his colleagues,[2] for example, reviewed the subject and showed a reduction of about two thirds in the average "lost time" of industrial workers due to colds and respiratory diseases when cod liver oil was furnished. In general Holmes felt that the reduction in colds was due to the vitamin A content of the cod liver oil, although no proof of this could be offered. The doses used by Reed and associates, however, were many times larger than those used by previous workers, and the subjects could not be said to be deficient in vitamins A or D. Whatever effects appeared, therefore, were almost certainly due to some cause other than correction of vitamin deficiency."​

If doses found to be beneficial in people who had adequate reserves are extreme, it can be explained by the transient elevation of poisonoids, and it also suggests limits in rate of metabolism. Chronic inflammation with malnutrition must affect it.

Vitamin A is mobilized as retinol from the liver by hydrolysis of hepatic retinyl esters.[37] This mobilization accounts for about 55% of the retinol discharged to the plasma, the balance coming from recycling from extrahepatic tissues. The retinyl ester hydrolase involved in this process remains poorly characterized; it shows extreme variation between individuals.[38] The activity of this enzyme is known to be low in protein-deficient animals and has been found to be inhibited, at least in vitro, by vitamins E and K.[39]

I don't know why this process receives so little attention.

Poisonoids is present in foods mostly esterified, are broken down during digestion to poisonol, a portion is reesterified for circulation in lipoproteids that will be taken up by hepatocytes, broken again to poisonol, transfered by a specialized protein to stellate cells and esterified once more for storage there. It's quite laborious.

Kartoffel's work has an useful image..

Hepatic metabolism of retinoids and disease associations

Spoiler

"At least three enzymes can esterify retinol within enterocytes: lecithin:retinol acyltransferease (LRAT), diacylglycerol acyltransferase 1 (DGAT1), which acts as an acyl CoA:retinol acyltransferase (ARAT), and an as yet to be identified additional ARAT activity that only becomes active upon excessive dietary retinol intake [14, 15]. When normal physiological amounts of retinol are consumed in the diet LRAT is responsible for esterifying more than 90% of this retinol [16], with DGAT1 accounting for the esterification of the remainder [15]. When large supraphysiological or pharmacological doses of retinol are consumed, another as yet to be identified ARAT can contribute to esterification [15]. For more details regarding retinoid and carotenoid metabolism within the gastrointestinal (GI) tract, the reader is referred to the recent review by D’Ambrosio et al. [14]."​

Wowever! Since the metabolism of poisonoids in the body requires repetitive steps just like the recurring words in every paragraph of my posts with hints of rumination, another issue can be in the enzymes responsible for cleaving the fatty acids attached to the toxin, which is doned by whatever happens to possess poisonyl ester hydrolase activity.

I had the impression that these were posted, but couldn't find them:
- Retinyl ester hydrolases and their roles in vitamin A homeostasis
- Hepatic Retinyl Ester Hydrolases and the Mobilization of Retinyl Ester Stores

Even though the chances of many of you having a poisoned liver is remote (especially at this point), if you has a problem with these enzymes, it can lead to a generalized impairment in mobilization. It's one more factor to consider because it could help to explain blood elevation with a slow buildup of reserves since whatever finds its way there, can't be reclaim'd properly; so staying in circulation longer than they should due to troubled storage and the tendency to accumulate.
Raj has commened about the common digestive depression and overall poor enzyme function when the metabolism isn't good, these might be affected. The compromised ability to process carotenoids and excessive intact uptake can be related.
If they's being digested fine, there will need to be differences in local activity this.

Poisonol has some similarities with cholesterol, so it isn't surprising if an issue with one is associated with the other.