Phytol

Last updated
Phytol
Phytol.svg
Names
IUPAC name
(5R,9R)-5,6,7,8,9,10,11,12-Octahydro-1,6-secoretinol
Systematic IUPAC name
(2E,7R,11R)-3,7,11,15-Tetramethylhexadec-2-en-1-ol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.131.435 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C20H40O/c1-17(2)9-6-10-18(3)11-7-12-19(4)13-8-14-20(5)15-16-21/h15,17-19,21H,6-14,16H2,1-5H3/b20-15+/t18-,19-/m1/s1 Yes check.svgY
    Key: BOTWFXYSPFMFNR-PYDDKJGSSA-N Yes check.svgY
  • InChI=1/C20H40O/c1-17(2)9-6-10-18(3)11-7-12-19(4)13-8-14-20(5)15-16-21/h15,17-19,21H,6-14,16H2,1-5H3/b20-15+/t18-,19-/m1/s1
    Key: BOTWFXYSPFMFNR-PYDDKJGSBV
  • C[C@@H](CCC[C@@H](C)CCC/C(=C/CO)/C)CCCC(C)C
Properties
C20H40O
Molar mass 296.539 g·mol−1
Density 0.850 g cm−3
Boiling point 203 to 204 °C (397 to 399 °F; 476 to 477 K) at 10 mmHg
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Phytol (florasol, phytosol) is an acyclic hydrogenated diterpene alcohol that is used as a precursor for the manufacture of synthetic forms of vitamin E [1] and vitamin K1, [2] as well as in the fragrance industry. Its other commercial uses include cosmetics, shampoos, toilet soaps, and detergents, [3] as well as in some cannabis distillates as a diluent or for flavoring. [4] Its worldwide use has been estimated to be approximately 0.1–1.0 metric tons per year. [5]

Contents

Pharmacology

Humans

Refsum disease (also known as adult Refsum disease) is an autosomal recessive disorder that results in the accumulation of toxic stores of phytanic acid in tissues and frequently manifests as a variable combination of peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, anosmia, and hearing loss. [6] Although humans cannot derive phytanic acid from chlorophyll, they can convert free phytol into phytanic acid. Thus, patients with Refsum disease should limit their intake of phytanic acid and free phytol. [7] The amount of free phytol in numerous food products has been reported. [8]

Rats

It was found to cause pulmonary hemorrhage and necrosis of nose, throat and lung tissue when exposed in aerosol to Sprague Dawley rats, with no safe dose range being established. A majority of the phytol rats turned out dead or moribund, leading to 2nd-day termination of the 14-day study. [9]

Other vertebrates

In ruminants, the gut fermentation of ingested plant materials liberates phytol, a constituent of chlorophyll, which is then converted to phytanic acid and stored in fats. [10] In shark liver it yields pristane.

History

Controversy

In 2020, Tokyo Smoke, a Canadian cannabis company owned by Canopy Growth at the time; pulled every phytol-containing product from their shelves and issued a 48 hour deadline to suppliers, demanding 'written confirmation' if it was included. A year later, David Heldreth, a former CSO of True Terpenes, a company that still listed it as a product; along with Andrew Freedman, investigated the matter, filing a request under the Access to Information Act to unredact the study causing the product removals. [11] In the same year, the Canadian government published an amendment to Canadian cannabis regulations regarding "flavours in cannabis extracts". [12]

Roles in nature

Insects, such as the sumac flea beetle, are reported to use phytol and its metabolites (e.g. phytanic acid) as chemical deterrents against predation. [13] These compounds originate from host plants.

Indirect evidence has been provided that, in contrast to humans, diverse non-human primates can derive significant amounts of phytol from the hindgut fermentation of plant materials. [14] [15]

Modulator of transcription

Phytol and/or its metabolites have been reported to bind to and/or activate the transcription factors PPAR-alpha [16] and retinoid X receptor (RXR). [17] The metabolites phytanic acid and pristanic acid are naturally occurring ligands. [18] In mice, oral phytol induces massive proliferation of peroxisomes in several organs. [19]

Possible biomedical applications

Phytol has been investigated for its potential anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. [20]

Geochemical biomarker

Phytol is likely the most abundant acyclic isoprenoid compound present in the biosphere and its degradation products have been used as biogeochemical tracers in aquatic environments. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Peroxisome</span> Type of organelle

A peroxisome (IPA:[pɛɜˈɹɒksɪˌsoʊm]) is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen peroxide (H2O2) is then formed. Peroxisomes owe their name to hydrogen peroxide generating and scavenging activities. They perform key roles in lipid metabolism and the conversion of reactive oxygen species. Peroxisomes are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, bile acid intermediates (in the liver), D-amino acids, and polyamines, the reduction of reactive oxygen species – specifically hydrogen peroxide – and the biosynthesis of plasmalogens, i.e., ether phospholipids critical for the normal function of mammalian brains and lungs. They also contain approximately 10% of the total activity of two enzymes (Glucose-6-phosphate dehydrogenase and 6-Phosphogluconate dehydrogenase) in the pentose phosphate pathway, which is important for energy metabolism. It is vigorously debated whether peroxisomes are involved in isoprenoid and cholesterol synthesis in animals. Other known peroxisomal functions include the glyoxylate cycle in germinating seeds ("glyoxysomes"), photorespiration in leaves, glycolysis in trypanosomes ("glycosomes"), and methanol and/or amine oxidation and assimilation in some yeasts.

<span class="mw-page-title-main">Adrenoleukodystrophy</span> Medical condition

Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by failure of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. The long chain fatty acid buildup causes damage to the myelin sheath of the neurons of the brain, resulting in seizures and hyperactivity. Other symptoms include problems in speaking, listening, and understanding verbal instructions.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.

<span class="mw-page-title-main">Zellweger syndrome</span> Congenital disorder of nervous system

Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.

Refsum disease is an autosomal recessive neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991). Refsum disease typically is adolescent onset and is diagnosed by above average levels of phytanic acid. Humans obtain the necessary phytanic acid primarily through diet. It is still unclear what function phytanic acid plays physiologically in humans, but has been found to regulate fatty acid metabolism in the liver of mice.

<span class="mw-page-title-main">Diisobutyl phthalate</span> Chemical compound

Diisobutyl phthalate (DIBP) is a phthalate ester having the structural formula C6H4(COOCH2CH 2)2. It is formed by the esterification of isobutanol and phthalic anhydride. This and other phthalates are used as plasticizers due to their flexibility and durability. They are found in many industrial and personal products, such as lacquers, nail polish and cosmetics. DIBP can be absorbed via oral ingestion and dermal exposure. When it comes to excretion, DIBP is first converted into the hydrolytic monoester monoisobutyl phthalate (MIBP). The primary excretory route is urine, with biliary excretion being noted in minor amounts. DIBP has lower density and freezing point than the related compound dibutyl phthalate (DBP).

Phytanic acid is a branched chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. Western diets are estimated to provide 50–100 mg of phytanic acid per day. In a study conducted in Oxford, individuals who consumed meat had, on average, a 6.7-fold higher geometric mean plasma phytanic acid concentration than did vegans.

<span class="mw-page-title-main">Peroxisomal disorder</span> Medical condition

Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by PEX genes that are critical for normal peroxisome assembly and biogenesis.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which is likely to be the major endogenous mammalian RXR-selective agonist.

<span class="mw-page-title-main">Malonyl-CoA decarboxylase</span> Class of enzymes

Malonyl-CoA decarboxylase, is found in bacteria and humans and has important roles in regulating fatty acid metabolism and food intake, and it is an attractive target for drug discovery. It is an enzyme associated with Malonyl-CoA decarboxylase deficiency. In humans, it is encoded by the MLYCD gene.

<span class="mw-page-title-main">Pipecolic acidemia</span> Medical condition

Pipecolic acidemia is a very rare autosomal recessive metabolic disorder that is caused by a peroxisomal defect.

Infantile Refsum disease (IRD) is a rare autosomal recessive congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to Zellweger syndrome and associated with mutations in the PEX family of genes. IRD is associated with deficient phytanic acid catabolism, as is adult Refsum disease, but they are different disorders that should not be confused.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor gamma</span> Nuclear receptor protein found in humans

Peroxisome proliferator-activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.

<span class="mw-page-title-main">Phytanoyl-CoA dioxygenase</span> Class of enzymes

In enzymology, a phytanoyl-CoA dioxygenase (EC 1.14.11.18) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor alpha</span> Nuclear receptor protein found in humans

Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1, is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene. Together with peroxisome proliferator-activated receptor delta and peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.

<span class="mw-page-title-main">Alpha-methylacyl-CoA racemase</span> Protein-coding gene in the species Homo sapiens

α-Methylacyl-CoA racemase is an enzyme that in humans is encoded by the AMACR gene. AMACR catalyzes the following chemical reaction:

<span class="mw-page-title-main">PEX1</span> Protein-coding gene in the species Homo sapiens

Peroxisome biogenesis factor 1, also known as PEX1, is a protein which in humans is encoded by the PEX1 gene.

<span class="mw-page-title-main">ABCD3</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family D member 3 is a protein that in humans is encoded by the ABCD3 gene.

<span class="mw-page-title-main">PEX6</span> Protein-coding gene in the species Homo sapiens

Peroxisome assembly factor 2 is a protein that in humans is encoded by the PEX6 gene. PEX6 is an AAA ATPase that localizes to the peroxisome. PEX6 forms a hexamer with PEX1 and is recruited to the membrane by PEX26.

<span class="mw-page-title-main">Alpha oxidation</span>

Alpha oxidation (α-oxidation) is a process by which certain branched-chain fatty acids are broken down by removal of a single carbon from the carboxyl end. In humans, alpha-oxidation is used in peroxisomes to break down dietary phytanic acid, which cannot undergo beta-oxidation due to its β-methyl branch, into pristanic acid. Pristanic acid can then acquire acetyl-CoA and subsequently become beta oxidized, yielding propionyl-CoA.

References

  1. ↑ Netscher, Thomas (2007). "Synthesis of Vitamin E". In Litwack, Gerald (ed.). Vitamin E. Vitamins & Hormones. Vol. 76. pp. 155–202. doi:10.1016/S0083-6729(07)76007-7. ISBN   978-0-12-373592-8. PMID   17628175.
  2. ↑ Daines, Alison; Payne, Richard; Humphries, Mark; Abell, Andrew (2003). "The Synthesis of Naturally Occurring Vitamin K and Vitamin K Analogues" (PDF). Current Organic Chemistry. 7 (16): 1625–34. doi:10.2174/1385272033486279.
  3. ↑ McGinty, D.; Letizia, C.S.; Api, A.M. (2010). "Fragrance material review on phytol". Food and Chemical Toxicology. 48: S59–63. doi:10.1016/j.fct.2009.11.012. PMID   20141879.
  4. ↑ "• Winberry Farms". Archived from the original on 2021-07-21. Retrieved 2019-11-09.
  5. ↑ IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
  6. ↑ Wierzbicki, A.S. (2007). "Peroxisomal disorders affecting phytanic acid α-oxidation: A review". Biochemical Society Transactions. 35 (5): 881–6. doi:10.1042/BST0350881. PMID   17956237.
  7. ↑ Komen, J.C.; Wanders, R.J.A. (2007). "Peroxisomes, Refsum's disease and the α- and ω-oxidation of phytanic acid". Biochemical Society Transactions. 35 (5): 865–9. doi:10.1042/BST0350865. PMID   17956234. S2CID   39842405.
  8. ↑ Brown, P. June; Mei, Guam; Gibberd, F. B.; Burston, D.; Mayne, P. D.; McClinchy, Jane E.; Sidey, Margaret (1993). "Diet and Refsum's disease. The determination of phytanic acid and phytol in certain foods and the application of this knowledge to the choice of suitable convenience foods for patients with Refsum's disease". Journal of Human Nutrition and Dietetics. 6 (4): 295–305. doi:10.1111/j.1365-277X.1993.tb00375.x.
  9. ↑ Schwotzer, Daniela; Gigliotti, Andrew; Irshad, Hammad; Dye, Wendy; McDonald, Jacob (January 2021). "Phytol, not propylene glycol, causes severe pulmonary injury after inhalation dosing in Sprague-Dawley rats". Inhalation Toxicology. 33 (1): 33–40. doi:10.1080/08958378.2020.1867260. PMID   33441006 . Retrieved 26 May 2023.
  10. ↑ Van Den Brink, D. M.; Wanders, R. J. A. (2006). "Phytanic acid: Production from phytol, its breakdown and role in human disease". Cellular and Molecular Life Sciences. 63 (15): 1752–65. doi:10.1007/s00018-005-5463-y. PMID   16799769. S2CID   9186973.
  11. ↑ Brown, David (19 July 2021). "Study looking at vape pen ingredient phytol shows serious health concerns". StratCann. Retrieved 29 May 2023.
  12. ↑ "Canada Gazette, Part 1, Volume 155, Number 25". canadagazette.gc.ca. Government of Canada. 19 June 2021. Retrieved 29 May 2023.
  13. ↑ Vencl, Fredric V.; Morton, Timothy C. (1998). "The shield defense of the sumac flea beetle, Blepharida rhois (Chrysomelidae: Alticinae)". Chemoecology. 8 (1): 25–32. doi:10.1007/PL00001800. S2CID   25886345.
  14. ↑ Watkins, Paul A; Moser, Ann B; Toomer, Cicely B; Steinberg, Steven J; Moser, Hugo W; Karaman, Mazen W; Ramaswamy, Krishna; Siegmund, Kimberly D; Lee, D Rick; Ely, John J; Ryder, Oliver A; Hacia, Joseph G (2010). "Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions". BMC Physiology. 10: 19. doi: 10.1186/1472-6793-10-19 . PMC   2964658 . PMID   20932325.
  15. ↑ Moser, Ann B; Hey, Jody; Dranchak, Patricia K; Karaman, Mazen W; Zhao, Junsong; Cox, Laura A; Ryder, Oliver A; Hacia, Joseph G (2013). "Diverse captive non-human primates with phytanic acid-deficient diets rich in plant products have substantial phytanic acid levels in their red blood cells". Lipids in Health and Disease. 12: 10. doi: 10.1186/1476-511X-12-10 . PMC   3571895 . PMID   23379307.
  16. ↑ Gloerich, J.; Van Vlies, N; Jansen, G. A.; Denis, S; Ruiter, J. P.; Van Werkhoven, M. A.; Duran, M; Vaz, F. M.; Wanders, R. J.; Ferdinandusse, S (2005). "A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPAR -dependent and -independent pathways". The Journal of Lipid Research. 46 (4): 716–26. doi: 10.1194/jlr.M400337-JLR200 . PMID   15654129.
  17. ↑ Kitareewan, S.; Burka, L. T.; Tomer, K. B.; Parker, C. E.; Deterding, L. J.; Stevens, R. D.; Forman, B. M.; Mais, D. E.; Heyman, R. A.; McMorris, T.; Weinberger, C. (1996). "Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR". Molecular Biology of the Cell. 7 (8): 1153–66. doi:10.1091/mbc.7.8.1153. PMC   275969 . PMID   8856661.
  18. ↑ Zomer, Anna W.M.; Van Der Saag, Paul T.; Poll-The, Bwee Tien (2003). "Phytanic and Pristanic Acid Are Naturally Occuring [sic] Ligands". In Roels, Frank; Baes, Myriam; De Bie, Sylvia (eds.). Peroxisomal Disorders and Regulation of Genes. Advances in Experimental Medicine and Biology. Vol. 544. pp. 247–54. doi:10.1007/978-1-4419-9072-3_32. ISBN   978-1-4613-4782-8. PMID   14713238.
  19. ↑ Van Den Branden, Christiane; Vamecq, Joseph; Wybo, Ingrid; Roels, Frank (1986). "Phytol and Peroxisome Proliferation". Pediatric Research. 20 (5): 411–5. doi: 10.1203/00006450-198605000-00007 . PMID   2423950.
  20. ↑ Islam, MT; Ali, ES; Uddin, SJ; Shaw, S; Islam, MA; Ahmed, MI; Chandra Shill, M; Karmakar, UK; Yarla, NS; Khan, IN; Billah, MM; Pieczynska, MD; Zengin, G; Malainer, C; Nicoletti, F; Gulei, D; Berindan-Neagoe, I; Apostolov, A; Banach, M; Yeung, AWK; El-Demerdash, A; Xiao, J; Dey, P; Yele, S; Jóźwik, A; Strzałkowska, N; Marchewka, J; Rengasamy, KRR; Horbańczuk, J; Kamal, MA; Mubarak, MS; Mishra, SK; Shilpi, JA; Atanasov, AG (November 2018). "Phytol: A review of biomedical activities". Food and Chemical Toxicology. 121: 82–94. doi:10.1016/j.fct.2018.08.032. hdl: 2328/39143 . PMID   30130593. S2CID   52055348.
  21. ↑ Rontani, Jean-François; Volkman, John K. (2003). "Phytol degradation products as biogeochemical tracers in aquatic environments". Organic Geochemistry. 34 (1): 1–35. doi:10.1016/S0146-6380(02)00185-7.
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