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Alcohol and Vitamin A metabolism
"In the toxic burst hypothesis, alcohol-induced aberrations in hepatic retinoid metabolism results in a toxic burst of transcriptionally active retinoid metabolites, presumable generated by CYP2E1, which directly contribute to the development of alcoholic liver disease [25]."
"With regard to the toxic burst hypothesis, Dan et al. studied the toxicity of polar retinol metabolites in the pathogenesis of alcohol-induced liver disease, finding them to be cytotoxic to HepG2 cells and primary rat hepatocytes [74]."
Wow
You mentioned the connection between liver obesity and vitamin A. You may be interested in this.
Quote from Armin on August 2, 2021, 9:59 amQuote from Даниил on August 2, 2021, 9:39 amQuote from Neilky on September 28, 2019, 8:55 amFound this really interesting as I am suffering from periodic blurred vision and have a retinol level of 3.0. The day after I consume alcohol my vision is pin sharp. My blood sugar is lower @ 5.2 which could explain it, however, I would not say my blood sugar is excessively high when I don't take alcohol @ 5.9. Having come off keto I am still consuming fatty meat and I do notice that high fat meals do increase blurring regardless of vitamin A. I believe I recall reading that fat mobilises retinol? If it's not the lower blood sugar improving my vision surely it is retinol reduction??
"Despite the evidence of depleted hepatic retinoid content in chronic alcoholics, it remains to be established whether dietary vitamin A supplementation would have a beneficial effect on liver pathology. Conflicting results have been published on the effect of vitamin A supplementation to rats chronically consuming alcohol, with one group reporting an enhancement of liver injury (increased lipid accumulation and increased indicators of steatohepatitis) [32,33]"
lol
lol indeed.
Interesting that chronic alcohol consumption bottoms out VA content. Pretty much confirms that alcohol consumption upregulates the ALDH and ADH levels and facilitates removal of VA.
I wonder if retynl esters can be removed via bile excretion
"Though this step has been less studied with regard to alcohol, it has been reported that hepatic microsomes isolated from alcohol-fed rats have increased retinaldehyde dehydrogenase activity, which was associated with the depletion of hepatic retinoid observed in these animals [65]."
"Under physiological conditions, the catabolism of retinoic acid is catalyzed by cytochrome P450 enzymes. While the actions of CYP26A1, 26B1 and 26C1 in retinoic acid catabolism have been well established, particularly during embryogenesis, several other cytochrome P450 enzymes have also been posited to metabolize retinoic acid, including several members of the CYP2C family [67]. In the context of chronic alcohol consumption, decreased levels of hepatic retinoic acid have often been associated with enhanced breakdown of this transcriptionally active vitamin A metabolite. There are three lines of evidence which support this notion, (1) decreased steady state levels of retinoic acid in the liver of alcohol-fed rodents (see above); (2) direct evidence of increased retinoic acid breakdown [27,45,46]; and (3) increased levels of polar retinoic acid metabolites, such as 4-oxo-retinoic acid and 18-hydroxy-retinoic acid, in the liver of alcohol-fed rodents [25,26,45,68]. Chronic alcohol consumption is known to induce the cytochrome P450 enzyme CYP2E1 [69]. Enhanced cytochrome P450 activity was associated with decreased hepatic retinoid content since some of the first feeding experiments in rodents were performed [18], the hypothesis that retinoic acid is metabolized in the alcoholic liver by CYP2E1 has been borne out by studies using a CYP2E1 inhibitor (chlormethiazole; CMZ). Treatment with this compound has been shown to normalize hepatic retinoic acid levels and prevent the appearance of retinoic acid metabolites in a dose-dependent manner [25,26,68]."
In the second case, glucuronidation is probably more preferable.
So, is the alcohol harmful or helpful in getting rid of vitamin A from the liver? Is it making the liver dump in a harmful way, or helpful way? What if we jack up the bile fluid and up the fiber intake, along with a good B-complex vitamin?
Quote from Moebius on August 2, 2021, 5:35 pmSo, is the alcohol harmful or helpful in getting rid of vitamin A from the liver? Is it making the liver dump in a harmful way, or helpful way? What if we jack up the bile fluid and up the fiber intake, along with a good B-complex vitamin?
It seems that retinol and its metabolites are excreted primarily through the bile. Retinol can to a lesser degree also be excreted via the urine. The concentration of vitamin A metabolites excreted in the bile is low when liver stores are low, but the excretion rate increases rapidly at higher liver reserves of the vitamin.
When looking at autoimmune illnesses, alcohol usage, tobacco usage and decaf coffee usage were listed as possible predispositions.
Alcohol strips the liver of vitamin A. Does it excrete it out of the body or just out of the liver, for it to land in other places, maybe in another form? Lemons also increase the ADH and ALDH pathways. Interestingly, citrus fruits are a possible trigger for eczema.
Tobacco strips the lungs and blood of retinol. Where does it go/turn into? Not sure, but maybe some metabolite like retinoic acid.
Decaf coffee is interesting. Decaf is worse for autoimmune diseases vs caffeinated. It never made much sense until I found out what caffeine does. Caffeine stimulates the contraction of the gallbladder. More bile is removed. Caffeinated coffee possibly negatively affects vitamin A metabolism but the caffeine does a decent job of getting rid of it via the gallbladder.
Interestingly, retinol is excreted via the feces and urine during times of acute infection. Almost like it wants it gone pronto.
I did find this, supporting the idea that retinoic acid also goes through the bile.
"We have studied excretion of oral 9-cis-retinoic acid in urine and feces in vigil rats and in bile in anesthetized rats. A proportion of 53 +/- 13% of the dose of 9-cis-retinoic acid administered was eliminated through the feces in 72 hr, and the urinary excretion was negligible. The prevalent form of elimination in feces and urine was the unchanged compound. Low biliary excretion was, for the most part, composed of metabolites."
https://pubmed.ncbi.nlm.nih.gov/8937864/
The secretion of metabolites of 14C-retinol and 14C-retinoic acid into the bile of the guinea pig and chick was studied. Within 6 hours after the intraportal injection of retinol or retinoic acid, the bile of the chick contained 5 and 20%, respectively, of the given dose whereas guinea pig bile contained 20 and 30%, respectively, of the total dose. This radioactivity in the bile was resolved by anion exchange chromatography into 3 fractions. The fractions contained non-ionic compounds, acidic substances like retinoic acid, and more polar acidic derivatives. About 12% of the injected dose of retinol was stored in the liver of both the chick and the guinea pig as retinyl ester, whereas retinoic acid was rapidly lost from the tissues of both animals. Since appreciable amounts of metabolites of retinol and retinoic acid are secreted in the bile of the guinea pig and chick as well as of the rat, this route for the removal of metabolic products of retinol from the liver may well be common in higher vertebrates.
https://academic.oup.com/jn/article-abstract/88/1/137/4777281?redirectedFrom=fulltext
Is it safer to excrete vitamin A in the form of retinol vs retinoic acid?
"In the toxic burst hypothesis, alcohol-induced aberrations in hepatic retinoid metabolism results in a toxic burst of transcriptionally active retinoid metabolites, presumable generated by CYP2E1, which directly contribute to the development of alcoholic liver disease [25]."
"With regard to the toxic burst hypothesis, Dan et al
Wow
You mentioned the connection between liver obesity and vitamin A. You may be interested in this.
However, from this study:
https://pubmed.ncbi.nlm.nih.gov/16115871/
"Examination by electron microscopy reveals a striking total absence of large lipid-containing droplets that normally store hepatic retinoid within the hepatic stellate cells of Lrat-/- mice. Despite the absence of significant retinyl ester stores and stellate cell lipid droplets, the livers of Lrat-/- mice upon histologic analysis appear normal and show no histological signs of liver fibrosis. "
Thus, the idea that retinol protects liver lipocytes has not been confirmed. Thus, the hypothesis indicated above was confirmed. So, vitamin A causes liver obesity and this is a fact (more precisely, the activation of P450 (CYP2E1) and the resulting retinol metabolites).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824476/
Smoking also activates the CYP2E1, and associated with NAFLD.
CYP2E1 is an enzyme that particularly participates in the metabolism of endogenous substrates, including acetone and fatty acids (abundant in the brain) [26] and exogenous compounds such as anesthetics, ethanol, nicotine, acetaminophen, acetone, aspartame, chloroform, chlorzoxazone, tetrachloride, and some antiepileptic drugs like phenobarbital. CYP2E1 can also activate toxic compounds and procarcinogens found in tobacco smoke and nitrosamine compounds [26–33]. CYP2E1 has an important player in the microsomal ethanol oxidizing system (MEOS).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259652/
CYP2E1, a membrane-bound protein, catalyzes the oxidation of a variety of endobiotics (such as retinoids and prostaglandins) and xenobiotics (such as drugs and alcohols)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314297/
It looks like some of the compounds in play may increase the metabolism of retinoids in a indiscriminate or haphazard manner.
Quote from Moebius on August 2, 2021, 5:35 pmSo, is the alcohol harmful or helpful in getting rid of vitamin A from the liver? Is it making the liver dump in a harmful way, or helpful way? What if we jack up the bile fluid and up the fiber intake, along with a good B-complex vitamin?
I now see it this way: there is retinol, which itself causes various symptoms (symptoms of of acute vitamin A poisoning). And there are retinol metabolites, they create other problems. Therefore, you can speed up detoxification at some stage. But if you don't speed up on the next one, you may experience an increase in some symptoms, because there will be a lot of some intermediate metabolite. Probably, genetic differences in the work of these enzymes give different symptoms in different people. Alcoholics eventually have lower concentrations in the liver, so I think drinking is useful for detoxification. In addition, there are also retinol and other metabolites in the tissues, so local detox acceleration can also be useful for these tissues. However, every time you eat, the liver releases bile(and VA), and since the bile is reabsorbed, VA enters in the tissues again. But keep in mind that if you drink a lot of alcohol at once, some forms of retinol will fall off. Therefore, I think it is necessary to ensure the smoothness of these processes.
I wonder what will happen if Grant drinks. Probably nothing terrible.
Quote from Даниил on August 4, 2021, 10:12 amQuote from Moebius on August 2, 2021, 5:35 pmSo, is the alcohol harmful or helpful in getting rid of vitamin A from the liver? Is it making the liver dump in a harmful way, or helpful way? What if we jack up the bile fluid and up the fiber intake, along with a good B-complex vitamin?
I now see it this way: there is retinol, which itself causes various symptoms (symptoms of of acute vitamin A poisoning). And there are retinol metabolites, they create other problems. Therefore, you can speed up detoxification at some stage. But if you don't speed up on the next one, you may experience an increase in some symptoms, because there will be a lot of some intermediate metabolite. Probably, genetic differences in the work of these enzymes give different symptoms in different people. Alcoholics eventually have lower concentrations in the liver, so I think drinking is useful for detoxification. In addition, there are also retinol and other metabolites in the tissues, so local detox acceleration can also be useful for these tissues. However, every time you eat, the liver releases bile(and VA), and since the bile is reabsorbed, VA enters in the tissues again. But keep in mind that if you drink a lot of alcohol at once, some forms of retinol will fall off. Therefore, I think it is necessary to ensure the smoothness of these processes.
I wonder what will happen if Grant drinks. Probably nothing terrible.
It's starting to make more sense.
When it comes to excretion of retinoic acid in bile, what happens if the retinoic acid in the bile is reabsorbed? Retinoic acid can no longer be converted back to retinol and stored. Does the liver attempt to sequester it once again in bile or does it just float around the body and cause problems until the immune system in triggered? Retinoic acid isn't water or fat soluble.
If VA was excreted as retinol and some were reabsorbed via the bile, the liver could at least just put it back in storage. Not the same with it comes to retinoic acid.
Quote from Armin on August 4, 2021, 10:30 amQuote from Даниил on August 4, 2021, 10:12 amQuote from Moebius on August 2, 2021, 5:35 pmSo, is the alcohol harmful or helpful in getting rid of vitamin A from the liver? Is it making the liver dump in a harmful way, or helpful way? What if we jack up the bile fluid and up the fiber intake, along with a good B-complex vitamin?
I now see it this way: there is retinol, which itself causes various symptoms (symptoms of of acute vitamin A poisoning). And there are retinol metabolites, they create other problems. Therefore, you can speed up detoxification at some stage. But if you don't speed up on the next one, you may experience an increase in some symptoms, because there will be a lot of some intermediate metabolite. Probably, genetic differences in the work of these enzymes give different symptoms in different people. Alcoholics eventually have lower concentrations in the liver, so I think drinking is useful for detoxification. In addition, there are also retinol and other metabolites in the tissues, so local detox acceleration can also be useful for these tissues. However, every time you eat, the liver releases bile(and VA), and since the bile is reabsorbed, VA enters in the tissues again. But keep in mind that if you drink a lot of alcohol at once, some forms of retinol will fall off. Therefore, I think it is necessary to ensure the smoothness of these processes.
I wonder what will happen if Grant drinks. Probably nothing terrible.
It's starting to make more sense.
When it comes to excretion of retinoic acid in bile, what happens if the retinoic acid in the bile is reabsorbed? Retinoic acid can no longer be converted back to retinol and stored. So does it just float around the body and cause problems until the immune system in triggered? Retinoic acid isn't water or fat soluble.
If VA was excreted as retinol and some were reabsorbed via the bile, the liver could at least just put it back in storage. Not the same with it comes to retinoic acid.
But the body somehow moves it, so it is dissolved in something, water-soluble or fat-soluble + there are also enzymes in the intestines.