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Capsanthin/Capsorubin/Canthaxanthin turning into some form of retinoic acid
A repost/summary of a thread which started on food coloring in sausages but went into how damaging the specific carotenoid canthaxanthin can be specifically for the eyes. Over-dosing on sun-tanning pills with canthaxanthin (~30 mg/day) for 2 months to 20 months could cause several yellow crystals to form on the retina which could take around 21 years to reverse after ceasing the supplementation.
Original thread:
https://ggenereux.blog/discussion/topic/beef-sausages-and-diarrhea/
Hi!
I am allergic to red bellpepper and paprika spice, even trace amounts.
I was at a sausage making farm when the owner said that almost all sausages have some form of paprika in it. It was because it makes sausages look less pale and supposedly this makes them easier to sell. I think color in the past might have inferred the freshness of a product since carotenoids degrade due to excess heat or just oxidation over time.
So whenever you read spices on a packet of sausage you should assume it is paprika or someother form of carotenoids extract in them and have to call the manufacturer to check what spices is in the sausage. For me it is just easier to avoid sausages and meat products in general.
Capsanthin, one of the carotenoids in red bellpeppers might cleave and with some form of enzymatic action, might turn into 2 molecules of all-trans retinoic acid.
The chemical formula for all-trans retinoic acid, according to wikipedia:
C20_H28_O2
A red bellpepper extract in oil is called paprika oleoresin which is commonly used to color foods (even french fries) and its color is mainly composed of:
Capsanthin (C40_H56_O3)
Capsorubin (C40_H56_O4)
Capsorubin is twice the atoms of retinoic acid and perhaps it could be transformed in the body to something that atleast mimicks retinoic acid. But its initial structure looks quite a bit different from that of all-trans retinoic acid.
For capsanthin, one end of its molecule looks very similar to retinoic acid and capsanthin might get cleaved in the middle by the enzyme BC01 (same enzyme that that can turn one beta-carotene into two retinaldehyde molecules). That one half of capsanthin might then be further transformed to something more similar to retinoic acid. The only difference I see between one end of a middle cleaved capsanthin and all-trans retinoic acid is the placement of capsanthin's -OH group and the addition of a double bonded oxygen, =O, close to where it was cleave by BC01.
All-trans retinoic acid (from wikipedia):
Capsanthin (from drugfuture.com):
Canthaxanthin (from https://lktlabs.com/product/canthaxanthin/):
Searching for "food grade color 1971" I didn't find anything definitely either. I do find this food chemical called "Canthaxanthine" in this official 1971 Indian report:
https://archive.org/download/gov.in.is.6405.1971/is.6405.1971.pdf
I attached a screenshot from that report, and if it is what they mean on your label with "Food grade color 1971" then that is yet another carotenoid, with trans-canthaxanthine also being quite similar in its main structure to that of all-trans retinoic acid. A middle cleave of trans-canthaxanthine and then some oxidation might just turn it into all-trans retinoic acid.
@Ourania says this:
"@david and @jude Thank you for this interesting point.
I notice that on French Wikipedia https://fr.wikipedia.org/wiki/Canthaxanthine it says that canthaxanthine is not a good idea as it brings night vision problems, crystals in the retina, hepatic injury, aplasic anaemia etc...
On English/US wiki all this is not mentioned.
The good news is: on the French Wikipedia they say that the problems are not permanent and disappear when the use of canthaxanthine is discontinued. Just a few years to go before we are rid of this problem!"
On the English wiki I do find the mention of problems with canthaxanthine but they try to say that is no problem in smaller amounts. Even though the page starts off by mentioning how canthaxanthine bioaccumulates in fish.
The wikipedia page on canthaxanthine, try to say that it is totally fine unless overconsumed but seems to ignore the possibility of bioaccumulation:
"In the late 1980s, the safety of canthaxanthin as a feed and a food additive was drawn into question as a result of a completely un-related use of the same carotenoid. A reversible deposition of canthaxanthin crystals was discovered in the retina of a limited number of people who had consumed very high amounts of canthaxanthin via sun-tanning pills – after stopping the pills, the deposits disappeared and the health of those people affected was fully recovered. However, the level of canthaxanthin intake in the affected individuals was many times greater than that which could ever be consumed via poultry products - to reach a similar intake, an individual would have to consume more than 50 eggs per day, produced by hens fed practical levels of canthaxanthin in their diets. Moreover, it was demonstrated by Hueber et al. that ingestions of canthaxanthin cause no long-term adverse effects, and that the phenomenon of crystal deposition on the retina is reversible and does not result in morphological changes.[20][21] ".
https://en.m.wikipedia.org/wiki/Canthaxanthin
I found another explaination for problems with dark adapation and blurry vision which can be caused by the carotenoid canthaxanthine which seems to be commonly used as feed supplement, only to enhance color of animals and eggs, and it is given to chickens, egg laying hens and farmed salmon. Canthaxanthine occurs naturally in for example the chanterelle mushroom.
Getting rid of most canthaxanthine in the retina after an overdose (through for example sun-tanning supplements with canthaxanthine) might take anything from 9 to 20 years to reverse from a 2011 study. The 2011 study really only has one long-term measuring points, 0 and 20 years, with the exception of just one person being test at 9 years too, which is why there is three different pictures of this person. I attach those pictures at the end of the post and they are from the 2011 study which is called "Canthaxanthin Retinopathy: Long-Term Observations" by Arno Hueber et. al. It is available at sci-hub with the doi:
https://doi.org/10.1159/000323813
There is also a whole webpage which talks about safety experiments done for canthaxanthine and is published by INCHEM (Internationally Peer Reviewed Chemical Safety Information) which is a part of WHO (World Health Organisation). It brings up how dark adaption and blurry vision can come from canthaxantine crystals in the retina after overdosing on cathaxanthine. I think cathaxanthine can also cause obvious damage due to long-term accumulation, just like some fish are known to bioaccumulate it (as mentioned at wikipedia). Here is a quote from INCHEM's webpage on cathaxanthine crystals in the retina:
"In most cases, pigment deposition is not associated with any detectable functional changes, but occasionally there have been complaints of dazzle or blurred vision (Cortin et al., 1984; Hennekes et al., 1985; Philipp, 1985); visual field defects have been described in only one report (Ros et al., 1985). The EOG is normal or subnormal and dark adaptation may be delayed; scotopic vision after exposure to glare is reduced while the ERG is normal or with b-wave changes (BoudreauIt et al., 1983; Merge et al., 1984; McGuiness & Beaumont, 1985; Weber et al., 1985b; Hennekes et al., 1985; Philipp, 1985).
Twenty-five patients were re-examined 2-10 months after therapy with canthaxanthin and ß-carotene was discontinued. Dark adaptation and ERG had normalized, but the crystalline retinopathy and pigment epithelial defects showed no signs of reversibility (Weber & Goerz, 1986)."
https://inchem.org/documents/jecfa/jecmono/v22je09.htm
That INCHEM page also says this about where canthaxanthine seem to bioaccumulation in the human body, especially after knowingly overdosing canthaxanthine:
"Canthaxanthin was measured at autopsy in the tissues of 38 people, aged 22 to 96 years, none of whom were known to have receive canthaxanthin therapeutically or in sun-tanning preparations. The tissues examined were mesenteric [intesitinal support structure] and sub-cutaneous fat, skin, liver, spleen, and blood serum. The highest concentrations were found in omentum and sub-cutaneous fat (mean concentrations, 0.2 and 0.3 µg/g, respectively). The mean concentrations in other tissues were: liver, 0.08 µg/g; skin and spleen, 0.04 µg/g; and serum, 0.024 µg/ml (Hoffmann-La Roche, 1986).
Fat samples from mesenterium and omentum and a liver sample were taken at autopsy from a 71-year-old woman who had died of bronchial carcinoma. The patient had previously ingested approximately 45 mg canthaxanthin/day for four years (total dose approximately 65 g) in a sun-tanning preparation. The concentrations of canthaxanthin in omentum and mesenteric fat were 270 µg/g and 158 µg respectively; lower levels of 5 µg/g were found in the liver (Hoffmann-La Roche, 1986)."
Answer from Grant Genereux:
"Hi @david,
Thanks for sharing that info.
For it to take from 9 to 20 years to reverse sounds about right to me.
Grant"
Thanks for posting this. I sometimes have a bit of a red pepper addiction. And in the past, I remember using a lot of paprika just for looks. derp! I suppose this info is a good choice to send along to anyone who thinks carotenes are purely good.
In the first post I talk quite a bit about canthaxanthin. I just found out that a synonym for the keto-carotenoid canthaxanthin is "Chlorellaxanthin".
http://carotenoiddb.jp/Entries/CA00471.html
This made it sound like there might be quite a bit of canthaxanthin in the algae family chlorella. The Chlorella strain "Chlorella pyrenoidosais" is commonly sold as a health food supplement, and might possiblt have a bit of canthaxanthin in it. When I searched "chlorella cnathaxanthin pubmed" I found a 2006 study which is about extracting canthaxanthin from the strain Chlorella zofingiensis. The 2006 study is called: "Isolation and purification of canthaxanthin from the microalga Chlorella zofingiensis by high-speed counter-current chromatography"
https://pubmed.ncbi.nlm.nih.gov/16605091/
Also found this 1993 study about a certain chlorella specie under high light intensity and low nitrogen conditions degrade chlorophyll into canthaxanthin. The 1993 study is called "Accumulation of canthaxanthin in Chlorella emersonii":
"A strain of Chlorella emersonii grown under high light intensity and low nitrogen degrades its chlorophyll and synthesizes canthaxanthin as the major carotenoid. Nitrogen starvation or high light alone does not induce canthaxanthin production.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-3054.1993.tb00148.x
As a side note green algae is also the main producers of astaxanthin (not just canthaxanthin) and might have been more popular than canthaxanthin according to this 2014 study called "Chlorella zofingiensis as an Alternative Microalgal Producer of Astaxanthin: Biology and Industrial Potential":
"Astaxanthin is the major carotenoid found in certain marine animals, for example, in crab, the red pigment accounts for more than 80% of total carotenoids [21]. Because of the higher color intensity and better absorption by the digestive tract of salmonids, astaxanthin is preferred over canthaxanthin in aquatic farming [22]."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071588/#__ffn_sectitle
Two different studies: the first one supporting that canthaxanthin can turn into one type of retinoic acid (4-oxo-retinoic acid) and the second one supporting that excentric cleavage of beta-carotene, forming apo-carotenals, can turn into retinoic acid.
The first study is a 1995 cell study that shows that it is at least possible for some of a non-vitamin A carotenoid, canthaxanthin, under certain circumstances to be transformed into 4-oxo-retinoic acid. The study is called:
"Efficacy of All-trans-β-Carotene, Canthaxanthin, and All-trans, 9-cis-, and 4-Oxoretinoic Acids in Inducing Differentiation of an F9 Embryonal Carcinoma RARβ-lacZ Reporter Cell Line"
https://www.sciencedirect.com/science/article/abs/pii/S0003986185710892?via%3Dihub
"By the same criteria, β-carotene at 10 μM also induced differentiation, but less strongly and more slowly than the retinoic acids. In contrast, the oxocarotenoid (or xanthophyll) canthaxanthin, at 10 μM, had little effect on differentiation, unless preincubated in culture medium, from which 4-oxoretinoic acid was recovered and identified as a decomposition product."
The second study is a 1996 study called:
"In vivo biosynthesis of retinoic acid from beta-carotene involves an excentric cleavage pathway in ferret intestine"
https://doi.org/10.1016/S0022-2275(20)37592-1
It shows how excentric cleavage of beta-carotene can be turned into retinoic acid in ferret intestines by the transformation:
beta-carotene -> beta-apo-carotenals -> beta-apo-carotenoic acid -> retinoic acid
I am attaching two figures (Figure 1 and 6) from the study.
Here is a quote from the end of the study:
"Although the results of the present study do not allow us to determine with accuracy the exact importance of central versus excentric pathways in the metabolism of B-C [beta-carotene], this study demonstrates for the first time in vivo that a substantial amount of RA [retinoic acid] is formed via a pathway that bypasses retinaldehyde oxidation, i.e., by excentric cleavage. It is possible that some retinaldehyde results from the degradation of the beta-apocarotenals formed from an excentric pathway (Fig. 1) resulting in an underestimate of excentric cleavage. It has been shown that the incubation of beta-apo-8’-carotenals or beta-apo-12’-carotenals with human intestinal homogenates results in the production of retinaldehyde, but this pathway seems to be less important than the formation of RA in vitro, as the beta-apo-carotenals produced 2.7- to 6.6-times more RA than retinaldehyde (21). Moreover, the addition of citral to papo-carotenal incubations decreased the formation of RA by only 14% (21). It is interesting to note the results of the work of Sharma, Mathur, and Ganguly (31), who evaluated the relative biopotencies of beta-apo-carotenals compared with B-C. In a curative growth assay in the rat, the biopotencies were 72, 78, and 72% of that for B-C on a molar basis for beta-apo-8’, 10', and 12’-carotenal, respectively. However, the relative amount of vitamin A in the liver for the beta-ap0-12’-carotenal was only 20% of that for B-C, suggesting that a large fraction of this beta-apo-carotenal may be transformed into RA, while only a small fraction is ultimately reduced to the corresponding alcohol.
In summary, this study demonstrates unambiguously for the first time in vivo that an excentric cleavage mechanism of B-C metabolism is involved in the biosynthesis of RA in the ferret intestine. This excentric cleavage mechanism represents a quantitatively important pathway in the metabolism of B-C into RA."
PS. If anyone is interested to look more at different apo-carotenoids, apo-carotenals and apo-retinoic acids, then there is this extensive carotenoid database:
http://carotenoiddb.jp/
