Phytol

Leafly’s take

The Cannabis consumer’s online magazine had an interesting take on phytol that is used in vape cartridges. David Downs’ piece offers an alarming overview of safety missteps.

This post will offer a scientific overview of phytol suggesting it might be healthy in small amounts in edibles. Eat your veggies and dairy products, but don’t vape them!

What the beep were “they” thinking?

Phytol is the tail of the chlorophyll molecule found in green vegetables we are supposed to eat for optimal health. (See featured image) Propylene glycol and phytol are used as thinning agents in vaporizing pens for pulmonary delivery of cannabis products. [1] A recent study found that phytol, more so than propylene glycol, caused pulmonary injury in a rat model. [1] Let’s take a look at a recent review of phytol in cancer and many other things.[2] These points are part of the featured image.

• Phytol may kill cancer cells. Phytol may also injure normal cells at a high enough concentration. [2]
• Phytol is found in nut skins and in the chlorophyll bound form in plant leaves. [2]
• Liberation from the chlorophyll ring structure requires microbial digestion in the colon. [2].
• Phytol is metabolized to phytanic acid by microbes in the digestive tract and in lymph nodes. [2]
• Phytanic acid is converted to pristanic acid in the liver. [2]
• Phytol is almost as long as acyl chains of a typical phospholipid.

Eating phytol may be healthy

Tying up a frenzied few decades of research

A 2013 study out of Cairo Egypt used a combination of 5 mg/kg oral phytol a rat model of diabetes and molecular docking of phytol and metabolites to a crystal structure of PPARγ [3] This study added strength to early studies of the 2000s and late 1990s showing anti-diebetic effects of phytol and metabolites. [3] According to a study out of Osaka Japan, phytanic acid also appears to be a ligand of PPARα in the liver and brown adipocytes. In a mouse model of diet induced obesity, dietary phytol had protective effects in wild type mice but not PPARα knockout mice. [4] Dozens of interesting studies demonstrating health benefits of phytol and metabolites in obesity and diabetic studies have been omitted from this post. References [3] and [4] will have to suffice in summing the health benefits of phytol adn metabolites while totally skipping the benefits of vitamins E and K, or which phytol is part of the molecular structure.

Eating too much phytol may be bad

Phytanic acid is degraded by phtanoyl-CoA dioxygenase. This enzyme is responsible for degradation of branch chained fatty acids. According to the UniProt.org entry, variants in the gene that code for this protein are responsible for Rfsum’s Disease. Refsum’s Disease is characterized by deficits. While phytol in plant and dairy products might have positive health benefits, it would stand to reason that too much may overwhelm degradation pathways and mimic disease states.

Phytol in membranes

Phytol, metabolites, and Vitamins E and K will make their ways into lipid bilayers of our cells according to in vitro studies. These in vitro studies may more closely mimic vaping than feeding studies.

• NMR studies of phytol and phytanic acid at 20% mol percent in dipalmitoyl phosphatidyl choline (DPPC) supported a model in which oxygen groups of the terepenes interacted with the choline head group. [5]
• Vitamin K is a cofactor needed for normal blood clotting. PubChem lists dairy products, liver, egg yolks, and green leaf vegetables as being a good source of vitamin K. Another ²H-NMR studied the behavior of Vitamins K1 and K2 in dimyristoylphosphatidylcholine membranes. [5] Vitamin K is not readily miscible with DMPC. It forms whose chains are parallel to the acyl chains of DMPC. [6] Both vitamins decreased the order of the PMPC bilayers. [6] Imagin a raft of vitamin K floating around in a sea of phosphocholine (lecithin) based phospholipids.
• Overall Alpha-tocopherol, aka Vitamin E is a lipid soluble compound that is incorporated into lipid bilayers. As shown below, it has a phytol tail it uses to get into cell membranes.A study with small angle X-ray scattering and fluorescent techniques in phosphatidyl choline/cholesterol lipid layers showed no evidence that neither α-tocopherol nor γ-tocopherol had any membrane destabilizing effects. [7] Note that phosphatidyl choline is an outer leaflet phospholipid.
• Yet another 2H-NMR study examined the effect of α-tocopherol on spingomyelin and phosphatidyl ethanolamine inner leaflet pohspholipids. [8] In these experiments α-tocopherol composed 20% of the lipids in the bilayers. In these experiments the fatty acid on the 2^nd carbon of the glycerol backbone was contained double bonds as it would in a natural membrane. The authors found α-tocopherol associated with regions of negative curvature called hexagonal II phase.

Some of these in vitro studies used concentrations that could never be achieved by simply ingesting phytol and its vitamins. Could these concentrations be achieved in our airways by vaping?

So what the beep were they thinking?

Were they thinking of the health benefits of phytol or that phytol is generally recognized as a safe food additive? Were they looking at a list of medical inhalants? Were they thinking that vaping is safer than smoking cancer causing pyrolysis products of tobacco or cannabis flower? Other terpenes are membrane soluble. The time might be right to consider if these terpenes are in high enough concentrations to cause airway membrane damage when vaped. These same terpenes often have health benefits when ingested.

References

1. Schwotzer D, Gigliotti A, Irshad H, Dye W, McDonald J. Phytol, not propylene glycol, causes severe pulmonary injury after inhalation dosing in Sprague-Dawley rats. Inhal Toxicol. 2021 Jan;33(1):33-40.
2. Bobe, G., Zhang, Z., Kopp, R., Garzotto, M., Shannon, J., & Takata, Y. (2020). Phytol and its metabolites phytanic and pristanic acids for risk of cancer: current evidence and future directions. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 29(2), 191–200. PMC free article
3. Elmazar, M. M., El-Abhar, H. S., Schaalan, M. F., & Farag, N. A. (2013). Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations. PloS one, 8(1), e45638. PMC free article
4. An JY, Jheng HF, Nagai H, Sanada K, Takahashi H, Iwase M, Watanabe N, Kim YI, Teraminami A, Takahashi N, Nakata R, Inoue H, Seno S, Mastuda H, Kawada T, Goto T. A Phytol-Enriched Diet Activates PPAR-α in the Liver and Brown Adipose Tissue to Ameliorate Obesity-Induced Metabolic Abnormalities. Mol Nutr Food Res. 2018 Mar;62(6):e1700688.
5. Yue JS, Cushley RJ. Deuterium NMR study of the interaction of phytanic acid and phytol with the head group region of a phospholipid bilayer. Evidence of magnetic orientation. Biochim Biophys Acta. 1990 Oct 22;1047(1):1-10.
6. Ausili A, Clemente J, Pons-Belda ÓD, de Godos A, Corbalán-García S, Torrecillas A, Teruel JA, Gomez-Fernández JC. Interaction of Vitamin K₁ and Vitamin K₂ with Dimyristoylphosphatidylcholine and Their Location in the Membrane. Langmuir. 2020 Feb 4;36(4):1062-1073.
7. DiPasquale M, Nguyen MHL, Rickeard BW, Cesca N, Tannous C, Castillo SR, Katsaras J, Kelley EG, Heberle FA, Marquardt D. (2020) The antioxidant vitamin E as a membrane raft modulator: Tocopherols do not abolish lipid domains. Biochim Biophys Acta Biomembr. 2020 Aug 1;1862(8):183189. PMC free article
8. Cavazos AT, Kinnun JJ, Williams JA, Wassall SR. (2020)Vitamin E – phosphatidylethanolamine interactions in mixed membranes with sphingomyelin: Studies by ²H NMR. Chem Phys Lipids. 2020 Sep;231:104910