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Riboflavin's role in an important VA detox pathway

Retinyl beta-glucuronide is a product of the enzymatic action of UDP-glucuronyltransferase/UDP-glucuronosyltransferase in the liver. It is water soluble and can be eliminated in bile and urine. It is one of the ways the body excretes VA.

Glucuronosyltransferases are responsible for the process of glucuronidation, a major part of phase II metabolism. Arguably the most important of the Phase II (conjugative) enzymes, UGTs have been the subject of increasing scientific inquiry since the mid-to-late 1990s.

https://en.wikipedia.org/wiki/Glucuronosyltransferase

Keep in mind that molybdenum and choline are key players in phase II detoxification.

Retinyl beta-glucuronide is a natural human metabolite of retinoic acid generated in the liver by UDP glucuonyltransferase. Glucuronidation is used to assist in the excretion of toxic substances, drugs or other substances that cannot be used as an energy source. Glucuronic acid is attached via a glycosidic bond to the substance, and the resulting glucuronide, which has a much higher water solubility than the original substance, is eventually excreted by the kidneys.

https://pubchem.ncbi.nlm.nih.gov/compound/Retinyl-beta-glucuronide

It turns out that riboflavin plays two key roles in this detox pathway. Firstly riboflavin is required for the conversion of retinol to RA:

Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) function as cofactors for a variety of flavoprotein enzyme reactions:

FAD is required to convert retinol (vitamin A) to retinoic acid via cytosolic retinal dehydrogenase

https://en.wikipedia.org/wiki/Riboflavin

Secondly, riboflavin is required for the conversion of RA to retinyl beta-glucuronide:

Hepatic drug metabolism during ethanol ingestion in riboflavin deficient rats.

Abstract
Riboflavin deficiency was induced by feeding rats a riboflavin-deficient diet for 1 month. In order to find out if there are any combined effects of ethanol and riboflavin deficiency on drug metabolism, a group of riboflavin-deficient rats were also given ethanol in their drinking water. At the end of the feeding period, hepatic drug-metabolizing enzyme activities were determined. The hepatic phospholipid and protein contents were the same in rats receiving a standard diet and in those on a riboflavin-deficient diet. However, ethanol ingestion in both groups enhanced significantly the phospholipid content. Ethanol ingestion also markedly enhanced the hepatic cytochrome P-450 concentration in rats fed either a standard or riboflavin-deficient diet. Ethoxycoumarin O-deethylase activity was significantly lower in riboflavin-deficient rat livers than in those of the controls. In both groups ethanol ingestion nearly doubled the activities. Aryl hydrocarbon hydroxylase activity was also significantly decreased during riboflavin deficiency. However, ethanol administration did not change the activities of this enzyme. UDP glucuronosyltransferase activity was slightly lower in riboflavin-deficient rat livers than in those fed a standard diet. No significant decrease was found in the epoxide hydrase activity in the riboflavin-deficient rats. However, the riboflavin-deficient rats had enhanced activity after the ethanol ingestion.

https://www.ncbi.nlm.nih.gov/pubmed/7414611

Riboflavin is apparently quite a safe supplement to take. Milk and meat is the main source of riboflavin in the diet. Riboflavin deficiency is an epidemic:

The study conducted by Lim and Yoon [20] in 1997 reported that 8.8% and 14.2% of Korean women (n = 38) had riboflavin deficient and low status, respectively, based on urinary excretion, which is in line with the prevalence of riboflavin deficiency and low status in Korean adults of this study. The national survey of UK in 2014 indicated the rate of riboflavin deficiency was 69% of British adults [26]. Whitfield et al. [35] reported that 67% of Canadian women (n = 51) had a suboptimal (low) status in 2014. The difference in rates of inadequate riboflavin status between the current study and the studies of UK and Canada may be due to a use of different biochemical index, EGRAC, in UK and Canadian studies. In this study, seven subjects (20%) of users of riboflavin supplements had inadequate riboflavin status. The mean riboflavin intake only from supplements of users with normal status was 6.80 mg/day (0.36–40 mg/day), but those of users with deficiency and low status was 0.94 mg/day (0.51–1.6 mg/day). Additional riboflavin intakes from supplements were low in users with inadequate status; therefore, it seems that the intake from supplements did not affect riboflavin status of them.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303837/

There is quite a bit of overlap between riboflavin deficiency and Hypervitaminosis A:

Riboflavin deficiency (also called ariboflavinosis) results in stomatitis including painful red tongue with sore throat, chapped and fissured lips (cheilosis), and inflammation of the corners of the mouth (angular stomatitis). There can be oily scaly skin rashes on the scrotum, vulva, philtrum of the lip, or the nasolabial folds. The eyes can become itchy, watery, bloodshot and sensitive to light.[27] Due to interference with iron absorption, even mild to moderate riboflavin deficiency results in an anemia with normal cell size and normal hemoglobin content (i.e. normochromic normocytic anemia). This is distinct from anemia caused by deficiency of folic acid (B9) or cyanocobalamin (B12), which causes anemia with large blood cells (megaloblastic anemia).[28] Deficiency of riboflavin during pregnancy can result in birth defects including congenital heart defects[29] and limb deformities.[30] Prolonged riboflavin insufficiency is also known to cause degeneration of the liver and nervous system.[15]

https://en.wikipedia.org/wiki/Riboflavin

Megadoses of riboflavin help prevent headaches, they don't know why. Are the megadoses helping to alleviate VA toxicity that is causing the headaches?

High doses of Vitamin B-2 (riboflavin) may help prevent migraine headaches, a European study reports in the journal Neurology. The beneficial effects in reducing migraine frequency appeared after a month of daily doses of 400 mg, and increased over the next two months, researchers said.

https://headaches.org/2007/10/25/vitamin-b-2/

Tim - you are really nailing it, thanks!! Making the riboflavin connection to the 'glucu-stuff' is great info. I had some on that subject archived from last year, but didn't know what to do with it and got off on something else. Here's one that might add something to the mix here. I've been studying a bit of carboxyl/hydroxyl chemistry lately, so it's an interesting coincidence to bring this review back into focus. I'm going to see if I can find the whole thing later on. BTW, just ate my first batch of mung sprouts.

Anticancer Res. 1983 May-Jun;3(3):171-80.

Pharmacologic disposition of chemopreventive retinoids (review).

The disposition of natural and synthetic retinoids, some of which effectively prevent cancer in carcinogen-dosed animals, varies with the structure of the compound. Disappearance of retinoids from serum may be either linear or exponential, and there may be a prolonged terminal elimination phase. Metabolism of these compounds is extensive, with little or no absorbed retinoid being excreted unchanged. Compounds giving rise to retinol can be stored as retinyl esters in the liver. In contrast, retinoids with a terminal carboxyl group are not stored but are metabolized on the ring and/or on the sidechain prior to excretion, which occurs often after conjugation of the metabolites with glucuronic acid. Isomerization of the double bonds in the sidechain may also occur. The metabolites of natural retinoids do not appear to possess more biological activity than the parent compounds, leading to the conclusion that their metabolism is, in general, degradative.

 

Here's a paper on Glucuronic Acid in Kombucha 

https://www.arpapress.com/Volumes/Vol14Issue1/IJRRAS_14_1_02.pdf

THE APPLICATION OF MICROBIAL GlcUA IN FOODS

It has been recognized that according to the increasing intake of xenobiotics nowadays, the quantity of GlcUA synthesized in human body is not sufficient for detoxication and elimination of xenobiotics and for promotion of fat-soluble endobiotics normal metabolism. The supplemental consumption of additional sources of GlcUA is advisable and GlcUA containing beverages fermented by Kombucha could help to solve the problem. Kombucha - fermented green or black tea drink is a source rich in GlcUA.

D-Glucurono-γ-lactone (DGL) that regulates the formation of D- GlcUA has been offered as a GlcUA source as well. The fact that the two compounds, DGL and GlcUA, are physiologically interchangeable opens a new perspective - a number of studies have revealed that even at high dosages the compound is relatively safe.

DGL can be found in minimal amounts naturally, with wine being the richest source with 20 mg/l. The DGL is safe at supplemental dosages (e.g. 500-3000 mg/day) and is short-lived in the humans; it is quickly absorbed via oral administration, metabolized and excreted in the urine. DGL hepatoprotective and detoxifying properties are reported.

 

Sidahora. 1995   PMID:11363369

The Kombucha mushroom: two different opinions.

Positive and negative views of the Kombucha mushroom, a popular remedy in Asia, are expressed. The Kombucha mushroom, used for centuries, is believed to have antibiotic tendencies and to strengthen the immune and metabolic systems. Studies show that the tea, made from fermented fungus, has high levels of B vitamins. Caution should be used during fermentation because exposing the fungus to sunlight may adversely affect the process. The mold in which the fungus grows may contain aspergillus, a fungal infection which may be fatal to HIV-positive persons. The tea is being commercialized as a stimulant of the immune system but is unpopular in the U.S. due to its toxicity risks. Public awareness messages must convey the danger of overstimulating the immune system of HIV-positive patients, whose immune systems are already overstimulated. Furthermore, the process of fermentation may encourage the growth of other organisms which produce medical complications in HIV-positive patients.

@hillcountry

Thanks mate, I've found truly life changing info learning more about how thiamine, riboflavin and other nutrients fit into the picture.

How did the sprouts turn out? Whenever I've done them myself they are never plump and big like the supermarket ones.

Do you think glucuronic acid in the diet is helpful? I'm skeptical due to the fact that it is an endogenously produced substance, in my experience I normally find the issue is with a lack of an essential nutrient/s that is needed to produce sufficient amounts of the endogenous substance. Kombucha seems to have a lot of fans which says something. A lot of Weston Price followers are into it, makes sense if it helps detox VA! When I've had homemade stuff it was sweet bubbly and delicious but the commercial stuff I've had is rank. I'd be happy to have a glass of red now and again for some glucu stuff!

@Tim  -  the sprouts were fine, with a second batch in the works. I ate 'em with a splash of balsamic. Nice crunch. The green skin separates-off with a bit of stirring and floats to the top in a bowl of water, so that's an easy process. They'll be a regular around here. 

Tend to agree with you about the endogenous thing. It seems I'm always looking for a short-cut, silver-bullet, etc., which has led me down some curious rabbit-holes for sure. Plenty of bogus info out there in nutrition-land. I like to pay attention to things that have long-histories of use and did successfully brew a champaigne-quality kombucha off-and-on in the 80's and 90's, prior to it being on all the store-shelves. It's fairly controlled at this point, per alcohol content for the commercial products anyways, but I'm ignorant about any QC/QA aspects on potential mold or bacteria problems. There must be a dozen brands in our area; almost as many as the micro-brewed beer pubs. I have one or two bottles of kombucha a month usually, and haven't had any bad experiences yet.

If I can find good evidence that exogenous glcUA is in-play metabolically, I'd happily up that consumption just on general principles. Sourcing a brand that is "breeding and brewing" with that goal in mind might take some time, but it sounds like there's some of it created no matter what the process parameters are. The paper did discuss some rather large quantities of glcUA produced, in many-gram-per-liter amounts, depending on temperature, process and ingredients. I would hazard a guess that it is the case that the body will use it, especially under conditions where it's needed due to some deficiency in endogenous production. It sounds like it's involved in a pretty critical set of catabolic pathways, so maybe it's just good insurance to include some now and then. Maybe a kombucha-cleanse has merit. Can't say as I've known anyone who did a kombucha-only thing. Didn't know the WP'ers were into it, but that does make sense. It seems like each dietary philosophy has its own share of detrimental practice and assumptions and then also some intuitively-derived ?? balancers of those. 

 

Glucuronidation of estrogens and retinoic acid and expression of UDP-glucuronosyltransferase 2B7 in human intestinal mucosa.     PMID:10997942

All-trans-retinoic acid was glucuronidated by all segments of intestine from both sexes at levels 50 to 80% of those found with human liver but quite low compared with estrogen glucuronidation.

To our knowledge, this is the first direct demonstration of glucuronidation of estrogens by human intestinal microsomes. Thus, in humans, the intestine may be considered as part of the overall mechanism of detoxification via glucuronidation.

Don't forget iodine and selenium(along with molybdenum) they are needed to activate B2.

https://imgur.com/a/mc4yEte

 

Yeah good point @orion. I get my iodine and selenium from fish.

Molybdenum is easy to get by eating beans however I struggle to digest them.

Mushrooms are high in riboflavin, they are so delicious as well, I think they play an important role in a low VA diet.

@hillcountry

Ah nice good to hear the mung sprouts were a success. I can't find any info on their molybdenum content. I know green peas have way less molybdenum than dried ones so I figure I can't just assume that mung sprouts will contain much of it. I think they will at least have some regardless they will be on the menu regularly.

Kombucha is known as a hangover cure and ethanol depletes glucuronic acid, yet kombucha itself contains some alcohol. It sounds like a non essential yet useful thing to include in one's diet. It's all the rage here in Australia but all the kombucha I've tried tastes like dilute vinegar. I think I know why this is: Live fermented beverages are unstable and will continue to ferment and produce bottle exploding CO2. Many customers are avoiding sugar also so that would explain why many are willing to drink something that tastes like vinegar. If I had a cafe I would produce the sweet bubbly delicious kombucha for customers. That would be incredibly popular.

I'm surprised this post didn't get more interest, here is the TL;DR:

  • ~70% of people are riboflavin deficient, these rates are higher among the elderly
  • Riboflavin is needed to convert retinol to RA and then to convert RA to a water soluble retinoid that can be eliminated from the liver and kidneys
  • Riboflavin deficiency symptoms have a lot of overlap with VA toxicity symptoms

These are exceptional (and rate limiting) deficiency rates, thiamin deficiency rates in the elderly are about 25% in comparison.

It has been very useful to me to be alerted to the possiblility of riboflavin deficiency.  In Dec I again experienced symptoms of thiamine deficiency which was a surprise as I thought I had my supplementation of thiamine pretty much nailed.  I think in fact I was lacking B2 and therefore wasn't able to utilise the thiamine I was taking.  I am now supplementing with B2 and the B1 deficiency symptoms are improving. 
I have also added small amounts of biotin as I almost certainly am not getting enough from my diet. 
Thanks for the TLDR summary.  I must admit I often find that the science stuff, although of great interest, is beyond my comprehension.  Having a short plain language summary is really helpful to me.