Quote from Dr. Garrett Smith on November 14, 2018, 9:39 pm

This is a bit complicated and will be worked into the retinoid X receptor (RXR) explanations later.

I will try to explain this in a logical progression after these research excerpts.  It all makes sense when it is put together.

Phytol, a Diterpene Alcohol from Chlorophyll, as a Drug against Neglected Tropical Disease Schistosomiasis Mansoni
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879229/

"Plants have always been used as a common source of medicine, both for traditional remedies and in industrialised products [7], [8]. Chlorophylls, found in all green vegetables, constitute an important source of an isoprenoid component, phytol (3, 7, 11, 15-tetramethyl-2-hexadecen-1-ol) [9]. It is an acyclic monounsaturated diterpene alcohol, present in vitamin K, vitamin E, and other tocopherols. Phytol is an aromatic ingredient used in many fragrance compounds and it may be found in cosmetic and non-cosmetic products [10]. In medicinal fields, phytol has shown antinociceptive and antioxidant activities [11] as well as anti-inflammatory and antiallergic effects [12]. Recent studies have revealed that phytol is an excellent immunostimulant, superior to a number of commercial adjuvants in terms of long-term memory induction and activation of both innate and acquired immunity [13]. Additionally, phytol and its derivatives have no cumulative inflammatory or toxic effects even in immuno-compromised mice [14]. Phytol has also shown antimicrobial activity against Mycobacterium tuberculosis [15], [16] and Staphylococcus aureus [17]."

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/

"Phytol (Table 2) is a diterpene (McGinty et al., 2010), present in cannabis extracts, as a breakdown product of chlorophyll and tocopherol. Phytol prevented vitamin A-induced teratogenesis by inhibiting conversion of retinol to a harmful metabolite, all-trans-retinoic acid (Arnhold et al., 2002). Phytol increased GABA expression via inhibition of succinic semialdehyde dehydrogenase, one of its degradative enzymes (Bang et al., 2002). Thus, the presence of phytol could account for the alleged relaxing effect of wild lettuce (Lactuca sativa), or green tea (Camellia sinensis), despite the latter's caffeine content."

Absorption of phytol from dietary chlorophyll in the rat.
https://www.ncbi.nlm.nih.gov/pubmed/6057491

"The results indicated that not more than 1-2% of chlorophyll phytol is available for absorption by the rat. Similarly, after the administration of whole spinach or spinach extract (not labeled) to rats, only about 1% of the total phytol content was absorbed into the intestinal lymph. Nearly all of the administered phytol was found in the feces and the contents of the colon, and was still largely in the form of pheophytin."

Absorption of chlorophyll phytol in normal man and in patients with Refsum's disease.
https://www.ncbi.nlm.nih.gov/pubmed/4177872

"This study was made to determine the extent of absorption of chlorophyll phytol from the intestine of man, and the importance of chlorophyll as a source of the phytanic acid that accumulates in Refsum's disease. Uniformly (14)C-labeled pheophytin a (the Mg-free derivative of chlorophyll a) was fed to normal human subjects and to patients with Refsum's disease. Feces were collected and analyzed. In all subjects, 90-95% of the administered radioactivity was recovered in the feces, still largely in the form of pheophytin a. The phytol radioactivity recovered in the feces averaged about 95% of that in the administered material, which indicates that there had been little absorption of the phytol moiety. Similarly, after 250 g of cooked spinach had been fed to a normal subject, almost the entire phytol content was found in the feces. Less than 5% of the ingested spinach phytol was accounted for in the thoracic duct lymph of another subject. It was concluded that not more than about 5% of the ingested chlorophyll phytol is absorbed by man, whether normal or afflicted with Refsum's disease. On this basis we conclude that the major portion of the phytanic acid that accumulates in Refsum's disease could not be derived from dietary chlorophyll."

Phytol/Phytanic Acid and Insulin Resistance: Potential Role of Phytanic Acid Proven by Docking Simulation and Modulation of Biochemical Alterations
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045638

"Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, we aimed to test the potential antidiabetic effect of phytol (250 mg/kg), the natural precursor of phytanic acid, a RXR ligand and/or pioglitazone (5 mg/kg) to diabetic insulin-resistant rats. Regarding the molecular docking simulation on PPARγ, phytanic acid, rather than phytol, showed a binding mode that mimics the crystal orientation of rosiglitazone and pioglitazone, forming H bonds with the same amino acids (S289, H 323, H 449 and Y 473), and the least energy level, which emphasizes their importance for PPARγ molecular recognition, activation, hence antidiabetic activity. In addition, docking on the RXRα/PPARγ heterodimer, revealed that phytanic acid has higher binding affinity and lesser energy score on RXRα, compared to the original ligand, retinoic acid. Phytanic acid binds by 3H bonds and shares retinoic acid in arginine (R 316). These results were further supported biochemically, where oral phytol and/or pioglitazone (5 mg/kg) improved significantly glucose homeostasis, lipid panel, raised serum adiponectin level and lowered TNF-α, reaching in most cases the effect of the 10 mg/kg pioglitazone. The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid."

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC275969/?page=1

"RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 microM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytenic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced [3H]-9cRA from RXR with Ki values of 4 microM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways."

Butterfat as a significant source of phytanic acid:

Effect of dairy fat on plasma phytanic acid in healthy volunteers - a randomized controlled study
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127790/

"In the current study we investigated to what extent milk fat from cows fed either "green" or "yellow" silage affects the concentration of phytanic acid in plasma in healthy young men and female.

The main finding of this study was a significant increase of plasma phytanic acid within both groups, regardless of cows feeding regime and test diet phytanic acid content. The higher increase in plasma phytanic acid in the control group compare to the phytanic acid group is opposed to what we have expected. This could be due to different compliance and/or random differences in phytanic acid metabolism between the groups. Since phytanic acid is not produced endogenously in human [25], the presence in the human body is of exogenous origin and ingested from the diet almost exclusively as preformed phytanic acid [26]. The exogenous origin of phytanic acid in human makes it reasonable to assume, that the increased concentration of phytanic acid found after the intervention, was due to an increase intake in this period."

Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all-trans-retinoic acid.
https://www.ncbi.nlm.nih.gov/pubmed/11896294

"Previous studies in our laboratory showed a synergistic interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in regard to teratogenic effects produced in mice (M. M. Elmazar et al., 2001, TOXICOL: Appl. Pharmacol. 170, 2-9). In the present study the influence of phytol and phytanic acid (a RXR-selective ligand) on the teratogenicity of retinol and the RAR-selective ligand all-trans-retinoic acid was investigated by coadministration experiments on day 8.25 of gestation in NMRI mice. Phytol and phytanic acid, noneffective when administered alone, did not potentiate the teratogenicity induced by retinol or all-trans-retinoic acid. On the contrary, phytol and phytanic acid greatly reduced retinol-induced teratogenic effects (ear anotia, tail defects, exencephaly). The effect of phytol on all-trans-retinoic acid teratogenesis was limited (only resorptions and tail defects were reduced). Pharmacokinetic studies in nonpregnant animals revealed that phytol coadministration with retinol reduced plasma levels of retinol and retinyl esters, and drastically reduced the levels of the teratogenic retinol metabolite, all-trans-retinoic acid. Phytanic acid also reduced the oxidative metabolism and teratogenic effects of retinol. These results indicate that phytol and phytanic acid did not synergize with retinol and all-trans-retinoic acid in our mouse teratogenesis model. Instead, phytol and phytanic acid effectively blocked the teratogenic effects of retinol by drastically reducing the metabolic production of all-trans-retinoic acid. Phytol and phytanic acid may be useful for the prevention of vitamin A teratogenicity."

Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475764/

"Thus, the ligand that possibly binds and activates RXRα heterodimerized with PPARβ(δ) cannot be a retinoic acid, as it would also bind RARγ and relieve the RARγ-mediated repression, thereby yielding abnormal LGs [lamelluar granulocytes]."

 

Phytanic acid is a retinoid X receptor ligand.
https://www.ncbi.nlm.nih.gov/pubmed/8617282

Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid.
https://www.ncbi.nlm.nih.gov/pubmed/17068359

Refsum's disease is "pseudohypervitaminosis A"
https://www.ncbi.nlm.nih.gov/pubmed/10673856

Refsum's Disease, an inability to break down phytanic acid, results in an excessive amount of phytanic acid accumulation in the tissues.  Just as too much Poison/"Vitamin A" overstimulates the RAR & RXR, excessive amounts of phytanic acid also can overstimulate the RXR.  This causes what has been referred to in the literature as "pseudohypervitaminosis A", because the symptoms mimic Poison/"Vitamin A" toxicity...because it is all related to overstimulation of the very same receptor.

http://www.worldblindunion.org/English/VisionHealth/eyeconditions/Pages/Retinitis-Pigmentosa.aspx (phytanic acid is another ligand of RXR, avoiding it in Refsum's Disease is helpful, so not to overstimulate the RXR)

So...unpacking all of the above and making the connections.

Phytol has beneficial effects.  Only ruminant animals (ex. cows) are able to obtain significant amounts of phytol from the breakdown of chlorophyll in plant matter, which is then broken down to phytanic acid and stored in their fat.  Humans cannot obtain significant amounts of phytol from chlorophyll in plant matter, so phytanic acid in humans comes from eating the fat of ruminant animals (ex. beef fat and butterfat). Phytol, once in the system, can be broken down into phytanic acid by humans.

As will be shown further (and is on the other DHA thread), Poison/"Vitamin A" as retinoic acids, is NOT the natural ligand of the RXR.  DHA, arachidonic acid, and phytanic acid ARE the natural ligands of the RXR, and deficiencies of these essential nutrients (whether through diet or genetics) have been shown to be related to all of the supposed "Vitamin A deficiency" diseases.764

 

However, t is the phytanic acid metabolite of phytol that we are mostly interested in, as it is a ligand for the retinoid X receptor.  This is very important.

 

 

Phytol breaks down to phytanic acid.  Phytanic acid is a ligand of the RXR, and has a higher binding affinity (strength of attraction between a ligand and receptor) than retinoic acid (a form of Poison/"Vitamin A").  This also suggests, as discussed elsewhere, that Poison/"Vitamin A" is NOT the natural ligand of the RXR and RAR, as multiple other ligands (DHA, arachidonic acid, and phytanic acid) bind to it with higher affinity.