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I3C decreased Vitamin A concentration in blood and liver?
I recently found this article: https://pubmed.ncbi.nlm.nih.gov/24000696/
The study was done in rats, but what stands out to me the most is the last line:
"Adding of I-3-C to the high-fat diets resulted to a significant reduction of vitamin A concentration in blood plasma by 12% (p=0.024) and in liver by 37% (p=0.002)."
I can't find any other mention online regarding I-3-C & retinols online (including DIM). However, it seems some of the proposed I-3-C benefits align with the relief of hypervitaminosis A. Considering the link/similarity between the detox of estrogens and Vitamin A in the body, this is interesting.
Thoughts?
Additionally, I found this: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180321
" We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high-affinity ligand 3,3´-diindolylmethane (DIM). I3C feeding robustly induced the AhR-target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy."
I3C induces aldh1 gene which is involved in Vitamin A metabolism.
"In the liver, ALDH1 contributes primarily to the metabolism of retinol (vitamin A) into retinoic acid (17). Because ALDH1 is also highly concentrated in HSCs, it is plausible that the primary function of ALDH1 in HSCs relates to its production of retinoids."
The ALDH1 gene and protein family is comprised of 3 isoforms, ALDH1A1 (Aldh1a1 in mouse), ALDH1A2, and ALDH1A3 [1–3], each of which is involved in the irreversible oxidative metabolism of the vitamin A metabolite retinal to form all-trans-retinoic acid (RA). Acute inflammation rapidly downregulates ALDH1A1 expression in whole liver.
If we induce things to go faster we need to make sure that there aren’t blockages further down in the pathways. ALDH is the step that makes things irreversible. Once retinaldehyde has become retinoic acid there is no going back. Before that the steps are reversible and vA can be put back into storage as retinyl esters.
That last bit, "Acute inflammation rapidly downregulates ALDH1A1 expression in whole liver", makes me wonder if the activation of ALDH by cruciferous vegetables is an evolved defense mechanism by plants that causes flooding of an animal's body with retinoic acid in order to harm it.
From what I've heard, the recommendation to consume plant compounds that activate glutathione production and other detox pathways in humans seems to ignore the fact that activation of those pathways is to expressly get rid of the harmful plant compounds themselves! Since when was it advisable to eat more toxins because they activate detox pathways? You need real nutrients (not xenobiotics) to support detox, and then you need an absence of incoming toxins and xenobiotics to allow detox of stored toxins to happen.
I get the feeling that I3C is intended to damage your body, like sulforaphane and goitrogens also found in crucifers. The conversion to retinoic acid is probably not the biggest bottleneck in healing Vitamin A toxicity, and it's probably harmful to "artificially" turn up that conversion process any higher by activation with plant compounds. As @jaj pointed out, you've got to have an evacuation plan for all that retinoic acid, and if you make too much of it at once you're just going to harm yourself further.
I3C is a ligand for the Aryl Hydrocarbon Receptor which controls retinoic acid catabolism as well.
https://cancerres.aacrjournals.org/content/57/14/2835.long
Livers from aryl hydrocarbon receptor-null mice showed a 3-fold increase in retinoids and a 65% decrease in retinoic acid metabolism. Levels of expression of the retinoic acid 4-hydroxylase, P450RAI, did not change, whereas cytochrome P4501A2 levels were lower in the null mouse, as shown earlier; however, this enzyme was found not to be active toward retinoic acid. These data suggest that aryl hydrocarbon receptor controls retinoic acid catabolism, through modulation of an unidentified target gene. Aldehyde dehydrogenases 1 and 2 were down-regulated markedly in the aryl hydrocarbon receptor-deficient mouse liver. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced cytochrome P4501A2 but not the aldehyde dehydrogenases in wild-type mice, suggesting that aryl hydrocarbon receptor is not involved directly in the down-regulation of this gene. Transglutaminase II, a retinoic acid-responsive gene product, was increased 2-fold, consistent with the liver fibrosis phenotype observed in the null mice. These findings suggest a molecular connection between xenobioticactivated receptor signaling and retinoid homeostasis.
@jaj I completely agree!
@wavygravygadzooks "Acute inflammation rapidly downregulates ALDH1A1 expression in whole liver", but in this case it looks like I3C is upregulating ALDH1 (having the opposite effect of inflammation), by increasing metabolism of retinol (vitamin A) into retinoic acid.
I completely agree with you regarding plant compounds. Typically, their compounds exist purely because it was somehow advantageous for survival, which more often than not means they are defensive in nature. I usually stay far away from them, and I also believe the glutathione response to plant chemicals is largely due to the body registering oxidative stress. However, from an evolutionary perspective, I don't believe any plant chemicals are inherently bad or good. Rather, they indiscriminately have a biological impact, and we the observer assign "positive" or "negative" associations to those biological effects. Many plant compounds like caffeine operate like a double edged sword with some positive biological effects and some negative, but I do believe in certain scenarios where that compound could have its uses medicinally.
What I find interesting in the study regarding the mice is the net effect of adding I3C on Vitamin A concentration:
"Adding of I-3-C to the high-fat diets resulted to a significant reduction of vitamin A concentration in blood plasma by 12% (p=0.024) and in liver by 37% (p=0.002)."
What I wish we knew is at what cost was the Vitamin A depleted? Did the mice have depleted glutathione? Evidence of oxidative stress? These are variables I really wish the study had measured/included.