Quote from puddleduck on June 29, 2023, 8:24 am

In “Naturally Occurring Eccentric Cleavage Products of Provitamin A β-Carotene Function as Antagonists of Retinoic Acid Receptors,”  we are reminded:

“It has been known since the 1930s that cleavage of the central double bond of β-carotene by vertebrates gives rise to retinaldehyde...”

But apparently this isn’t the only way the body processes β-Carotene:

“β-Carotene is cleaved eccentrically at double bonds other than the central one to yield β-apocarotenals and β-apocarotenones (8, 9, 10), molecules that have been detected in foods (11) and in the blood of both humans (12) and animals (13), but whose function in these is unknown. Here, we show that some of these compounds (particularly β-apo-14′-carotenal, β-apo-14′-carotenoic acid, and β-apo-13-carotenone) function as antagonists of retinoic acid receptors α, β, and γ and block the ATRA-induced activation of endogenous genes that contain RAREs in their promoters. Moreover, these molecules directly compete for ATRA binding to all receptor subtypes, and in the case of β-apo-13-carotenone, the binding affinity is in the nanomolar range and comparable with ATRA itself.”

I have been curious to understand why vegans (specifically those who exclusively consume whole plant foods, usually but not always limiting or excluding added oils, and who often emphasize raw fruits and vegetables in their diets) have been so successful at reversing autoimmune diseases, for which those of us here blame chronic hypervitaminosis A.

Could these antagonists be part of the reason for their successes?

“Although the mechanisms responsible for the formation of the eccentric cleavage products of β-carotene in mammals are not fully known, it is clear that some of the long chain β-apocarotenals (e.g. 8′, 10′, 12′, 14′) are found in the plasma of humans (12) and experimental animals (13) and that these are increased under conditions of oxidative stress and high dietary doses of β-carotene (24). We have also found that all of these β-apocarotenals and, specifically, β-apo-13-carotenone are present in fresh cantaloupe and orange-fleshed melons (11); thus, these compounds may be absorbed directly from the diet.”

When I ate watermelon and cantaloupe for breakfast three days in a row (without any added dietary fats those days), providing a food-based dose of 500 mcg of RAE daily...I felt perfectly fine. My head was fine. My digestion was fine.

I figured that was because I wasn’t absorbing the caeotenoids.

But since reading the above this morning, I have to wonder if β-apo-13-carotenone (and other antagonists) might be partially responsible for the rapid recoveries individuals such as Michele, who had severe meibomian gland dysfunction but recovered completely within a year-and-a-half of switching to a fruit-based diet from Grant’s “prison food” diet, experience on a plant-based diet.

My question: is it possible plant-based retinoic acid receptor antagonists could be especially beneficial for individuals who have been accutane poisoned?

“We then analyzed the plasmas of six free-living individuals and found the plasma concentration of β-apo-13-carotenone to be 3.8 ± 0.6 nm. Importantly, this is in the range of normal concentrations of retinoic acid in plasma and approximately the same as the binding constant of the compound for the retinoid receptors. This would suggest that β-apo-13-carotenone can function at physiological concentrations as an endogenous modulator of retinoid signaling in humans.”

“Our results demonstrate that β-carotene can generate both RAR agonists (ATRA) and RAR antagonists (β-apo-14′-carotenal and β-apo-13-carotenone) depending on the extent of cleavage at the central C15–C15′ double bond or the C13–14 double bond, respectively.”

These researches believe too many antagonists could be a bad thing, which might explain the disastrous CARET trial:

“These findings may have implications for the unexpected and negative effects of high doses of β-carotene in human clinical trials of cancer prevention (25). An example is the now famous CARET trial, which, based on observational epidemiology, explored whether supplemental β-carotene would decrease incidence of lung cancer in a highly susceptible population, namely smokers and asbestos workers (26, 27). Surprisingly, the supplemented subjects had a higher incidence of disease, and the trial had to be halted early. It was apparent that the doses of β-carotene used in the trial (30 mg/day) were much higher than the range of normal dietary intakes associated with a decreased risk of disease in the observational studies (25).”

In “Beta Carotene: The Controversy Continues” (Alternative Medicine Review, Volume 5, #6, 2000 for Thorne Research, Inc.) Dr. Lyn Patrick writes:

“The CARET study evaluated the effect of 30 mg β-carotene and 25,000 IU retinyl palmitate versus placebo in 18,314 men and women. [61] Twenty-two percent of the study population were occupationally asbestos-exposed, 39 percent were former smokers, and 60 percent were current smokers. The trial was ended two years early, after approximately four years, when the incidence of lung cancer in the intervention group was found to be 28-percent higher and the incidence of mortality 17-per-cent higher than the placebo group. Those who were smoking during the study had an even higher risk of lung cancer: a relative risk of 1.42 (42-percent increase in incidence). In the participants who had stopped smoking at least two years prior to entry, the combination of β- carotene and retinol had a protective effect that did not reach statistical significance–a relative risk of 0.80 for diagnosis of lung cancer during the study period.”

Most of us here are familiar with that infamous study by now, and feel the insanely high dosage is likely the main problem.

But Dr. Patrick’s article is interesting, because she explains there’s a difference between naturally occurring beta-carotene and the synthetic form, which is 100% all-trans β-carotene.

“The efficient uptake of synthetic all-trans β-carotene and isomerization in the gut to 9-cis β-carotene appears to make the synthetic form more desirable for effective absorption.”

“But the tendency of synthetic β-carotene to alter normal serum trans/cis ratios in favor of the trans isomer may not be a beneficial effect. If, as theorized by You et al, the preferred absorption of all-trans isomers is a mechanism to control the production of 9-cis retinoic acid by the 9-cis β-carotenoid isomer, then artificial down-regulation of this important chemopreventive growth-regulator may not be wise.”

So what I’m getting from this is that supplementing ß-carotene has different physiological consequences than eating a piece of pumpkin pie.

“Clearly, more research is needed to fully understand the antioxidant mechanisms in β-carotenoid physiology. The isomerization of all-trans ß-carotene in the gut lumen to 9-cis ß-carotene is not a thermodynamically favored reaction and may be catalyzed enzymatically. The 9-cis ß-carotenoids do appear to have an advantage as antioxidants in preventing depletion of hepatic ß-carotene stores in the rat model; however; whether or not cis β-carotenoids act as antioxidants at the human gut surface is unclear.”

That part of her article was especially interesting to me. Synthetic ß-carotene supplementation depleted the rat’s liver stores of ß-carotene. Is that a good thing or a bad thing? I’ve got to lean towards it being a bad thing in this context...

“The possibility that β-carotene acts as a pro-oxidant and co-carcinogen in the lung tissue of smokers who smoke more than one pack per day has not been ruled out and the use of β-carotene (natural or synthetic) in heavy smokers or those exposed to significant amounts of airborne nitric oxides must be questioned, as we do not have enough information about the antioxidant deficiencies inherent in this population.”

But does naturally occurring ß-carotene within the food matrix (like, as in a cantaloupe melon or an orange, and not fiberless carrot juice) present the same problem?

I’ve gotta wonder if the issue here isn’t the excessive presence of retinoic acid receptor antagonists, but rather their lack...or a lack of balance between them and retinoic acid, potentially?

(It’s a leap either way, because nobody tested the CARET study participants’ blood levels for antagonists.)

Anyway, I’m not a biochemist and don’t really understand what I’m talking about here. Maybe all of these different forms are irrelevant, because none of them are needed by the body.

What do you guys think?