Mezerein

Last updated
Mezerein
Mezerein.svg
Names
Other names
meserein; 12β-[(E,E)-5-Phenyl-2,4-pentadienoyloxy]daphnetoxin; daphnetoxin,12-[(1-oxo-5-phenyl-2,4-pentadienyl)oxy]-,12-beta(E,E)]
Identifiers
3D model (JSmol)
1675867
ChemSpider
ECHA InfoCard 100.159.782 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 631-545-8
PubChem CID
UN number 2811
  • InChI=1S/C38H38O10/c1-21(2)36-30(44-27(40)18-12-11-15-24-13-7-5-8-14-24)23(4)37-26-19-22(3)29(41)35(26,43)33(42)34(20-39)31(45-34)28(37)32(36)46-38(47-36,48-37)25-16-9-6-10-17-25/h5-19,23,26,28,30-33,39,42-43H,1,20H2,2-4H3/b15-11+,18-12+/t23-,26-,28+,30-,31+,32-,33-,34+,35-,36+,37+,38-/m1/s1
    Key: DLEDLHFNQDHEOJ-UDTOXTEMSA-N
  • OC[C@]12O[C@H]1[C@H]1[C@H]3O[C@]4(O[C@]1([C@H]1[C@@]([C@@H]2O)(O)C(=O)C(=C1)C)[C@@H]([C@H]([C@@]3(O4)C(=C)C)OC(=O)/C=C/C=C/c1ccccc1)C)c1ccccc1
Properties
C38H38O10
Molar mass 654.712 g·mol−1
Melting point 258.0 to 262.0 °C; 496.4 to 503.6 °F; 531.1 to 535.1 K
Hazards [1]
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H315, H317
P261, P264, P272, P280, P302+P352, P321, P332+P313, P333+P313, P362, P363, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Mezerein is a toxic diterpene ester found in the sap of Daphne mezereum and related plants. Plants of the genera Euphorbiaceae and Thymelaeaceae possess a wide variety of different phorbol esters, which share the capacity of mimicking diacylglycerol (DAG) and thus activating different isoforms of protein kinase C. Mezerein was first isolated in 1975. It has antileukemic properties in mice, but it is also defined as a weak promoter of skin cancers in the same species. [2] All parts of the plants contain an acrid and irritant sap that contains mezerein, thought to be the principal poison. The sap is especially prevalent in the bark and berries.

Contents

Mezerein is highly liposoluble and can cause vomiting, diarrhea and burning of the mouth. When a large dose is taken, there can be shivering, dilation of the pupils, damage to the oral passages and the intestine and even death. It can also irritate the skin, resulting in redness by slight damage of the veins. Because of causing this redness, the sap used to be applied as rouge. [2]

History and alternative uses

Mezerein can be found in Daphne mezereum . [2] This plant has been used to make dyes, treat rheumatism and indolent ulcers and as a cosmetic. [3] [4] In homeopathy, the plant is used to treat primarily skin disorders but is also prescribed to treat anxiety related to digestive disorders and congestion. [5] Once the toxicity of the plant was discovered, these uses were abandoned. The toxicity also led to new uses. In extreme cases, the berries are used to commit suicide. [6]

Mezerein and daphnetoxin

The toxins mezerein and daphnetoxin are both present in the genus Daphne . Daphnetoxin has a structure similar to mezerein, with the phenyl-pentadienoyl component (top left of the mezerein structural diagram) missing. They are both PKC activators but with a different selectivity: mezerein exhibits antileukemic properties while daphnetoxin does not. [7]

Mechanism of action

Mezerein is a second stage tumor promoter. [8] According to the IPP model, tumorigenesis happens in three stages: initiation, promotion, and progression. In the first stage, initiation, a gene-mutation with change of function occurs. These mutations often occur in oncogenes or regulatory sequences. In the promotion stage, interaction with cellular signaling pathways takes place. This leads to growth advantage for initiated cells. In the last stage, progression, the tumor has become karyotypically instable: morphological changes in the normal chromosomal structure take place. This instability is caused by additional mutations. This leads to metastasis, hyperproliferation and loss of control by the cellular environment. There is an increased risk that the tumor cells will mutate other genes. Second stage tumor promoters like mezerein do not have the capacity to initiate tumors, but can create circumstances in which initiated cells are more susceptible to additional mutations or in which initiated cells have growth advantage. [9] [10] They do not cause mutations themselves: promotion happens through interference with cellular signaling pathways.

Mezerein and other phorbol esters interact with protein kinase C (PKC). Protein kinase C controls the cell cycle, so chemicals that interact with it can have pro-proliferative or anti-proliferative effects. PKC is normally activated by diacyl glycerol (DAG). Upon DAG binding to PKC, PKC's affinity for Ca2+ and membrane phosphoinositols is increased. After binding Ca2+, the DAG-PKC-Ca2+ complex is attached to the plasma membrane by binding to membrane phosphoinositols. Now, PKC can phosphorylate various substrates, affecting the activity of several intracellular pathways that regulate cell cycle and apoptosis among others. PKC binding to the plasma membrane is reversible, because after a short period of time DAG is enzymatically degraded, causing PKC to undergo a conformational change and detach from the membrane and stop phosphorylating substrates.

Mezerein binds to PKC instead of DAG. It has a higher affinity for PKC than DAG does, and it cannot be degraded as easily as DAG. Therefore, when mezerein is bound, PKC remains in the active conformation much longer than it normally does. Furthermore, when mezerein has bound to PKC, PKC no longer requires Ca2+ for activation. This causes overstimulation of the pathways PKC initiates, leading to more cellular proliferation and less apoptosis. [11]

However, it seems that chronic activation of PKC leads to a negative effect, that is, apoptosis. Furthermore, high doses of mezerein have been used to terminally differentiate cancer cells, preventing their growth. Thus, mezerein can have both carcinogenic and non-carcinogenic properties. Usually, low doses cause a beneficial effect and high doses cause a toxic effect. [12] [13]

Dose-response relationships

Decrease in fibronectin levels dose-response curve LETSP decrease dose-response curve.jpg
Decrease in fibronectin levels dose-response curve
Stimulation of 2-DG dose-response curve Stimulation of 2-deoxyglucose dose-response curve.jpg
Stimulation of 2-DG dose-response curve

Mezerein has been shown to have two effects in chick embryo fibroblasts (CEF cells) that are associated with cancer. These effects are stimulation of 2-deoxy-D-glucose (2-DG) transport and causing of fibronectin loss. These effects are known to correlate with tumorigenicity in mice. [14] Both effects are mediated by PKC. [15] [16] The ability of mezerein to decrease fibronectin levels is 46-fold lower than its ability to stimulate 2-DG transport. In related compounds, the difference between the two effects is usually 2- to 9-fold. This may have something to do with the weak tumorigenicity of mezerein.

The shape of the 2-DG transport dose-response curve has an optimum at a mezerein concentration of approximately 50 ng/mL. This is atypical, since a dose-response curve usually is S-shaped. The explanation for this behaviour is unknown. Possibly, at high concentrations, mezerein is converted by enzymes that have low affinity for it. That would lower the effective concentration and thus decrease the effects. In this picture, a NOAE-level can be observed between mezerein concentrations of 0 to approximately 0.09 ng/mL. The concentration that gives half-maximal effects is reached for a low concentration of mezerein: about 0.7 ng/mL.

The shape of the fibronectin-decrease curve is more usual, although not quite: the separate parts of the curve are all more or less linear, which is not the case in an S-shaped curve. In this case, a maximum dose can be determined: above concentrations of about 103 ng/mL the effect remains more or less stable. A NOAE-level is visible for concentrations of up to 1 ng/mL of mezerein. The concentration that gives half-maximal effect is approximately 90 ng/mL. The difference with the half-maximal concentration for 2-DG transport is remarkable. Mezerein causes a 46-fold lower effect for fibronectin decrease than for 2-DG stimulation, and apparently only causes this effect at high concentrations. This might also correlate with mezerein being a weak tumor promoter.

Related Research Articles

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

12-<i>O</i>-Tetradecanoylphorbol-13-acetate Chemical compound

12-O-Tetradecanoylphorbol-13-acetate (TPA), also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate (PMA) is a diester of phorbol. It is a potent tumor promoter often employed in biomedical research to activate the signal transduction enzyme protein kinase C (PKC). The effects of TPA on PKC result from its similarity to one of the natural activators of classic PKC isoforms, diacylglycerol. TPA is a small molecule drug.

<span class="mw-page-title-main">Calcium signaling</span> Intracellular communication process

Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.

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

Phorbol is a natural, plant-derived organic compound. It is a member of the tigliane family of diterpenes. Phorbol was first isolated in 1934 as the hydrolysis product of croton oil, which is derived from the seeds of the purging croton, Croton tiglium. The structure of phorbol was determined in 1967. Various esters of phorbol have important biological properties, the most notable of which is the capacity to act as tumor promoters through activation of protein kinase C. They mimic diacylglycerols, glycerol derivatives in which two hydroxyl groups have reacted with fatty acids to form esters. The most common and potent phorbol ester is 12-O-tetradecanoylphorbol-13-acetate (TPA), also called phorbol-12-myristate-13-acetate (PMA), which is used as a biomedical research tool in contexts such as models of carcinogenesis.

<span class="mw-page-title-main">Phorbol esters</span> Group of chemical compounds

Phorbol esters are a class of chemical compounds found in a variety of plants, particularly in the families Euphorbiaceae and Thymelaeaceae. Chemically, they are ester derivatives of the tetracyclic diterpenoid phorbol.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Chimerin 1</span> Protein-coding gene in the species Homo sapiens

Chimerin 1 (CHN1), also known as alpha-1-chimerin, n-chimerin, is a protein which in humans is encoded by the CHN1 gene.

<span class="mw-page-title-main">C1 domain</span>

C1 domain binds an important secondary messenger diacylglycerol (DAG), as well as the analogous phorbol esters. Phorbol esters can directly stimulate protein kinase C, PKC.

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

Protein kinase C alpha (PKCα) is an enzyme that in humans is encoded by the PRKCA gene.

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

Protein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.

<span class="mw-page-title-main">PRKCB1</span> Protein-coding gene in the species Homo sapiens

Protein kinase C beta type is an enzyme that in humans is encoded by the PRKCB gene.

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

Protein kinase C gamma type is an enzyme that in humans is encoded by the PRKCG gene.

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

Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene. PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.

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

Protein kinase C eta type is an enzyme that in humans is encoded by the PRKCH gene.

<span class="mw-page-title-main">Chimerin 2</span> Protein-coding gene in the species Homo sapiens

Chimerin 2 (beta-chimaerin) is a protein that in humans is encoded by the CHN2 gene.

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

Daphnin is a plant toxin with the chemical formula C15H16O9 and is one of the active compounds present in the Eurasian and North African genus Daphne of the Thymelaeaceae, a plant family with a predominantly Southern Hemisphere distribution with concentrations in Australia and tropical Africa.

Safingol is a lyso-sphingolipid protein kinase inhibitor. It has the molecular formula C18H39NO2 and is a colorless solid. Medicinally, safingol has demonstrated promising anticancer potential as a modulator of multi-drug resistance and as an inducer of necrosis. The administration of safingol alone has not been shown to exert a significant effect on tumor cell growth. However, preclinical and clinical studies have shown that combining safingol with conventional chemotherapy agents such as fenretinide, vinblastine, irinotecan and mitomycin C can dramatically potentiate their antitumor effects. In phase I clinical trials, it was found to be safe to co-administer with cisplatin, but caused reversible dose-dependent hepatotoxicity.

<span class="mw-page-title-main">Tigilanol tiglate</span> Chemical compound

Tigilanol tiglate, sold under the brand name Stelfonta is a medication used to treat dogs with non-metastatic, skin-based (cutaneous) mast cell tumors (MCTs). The FDA is also approving Stelfonta to treat non-metastatic MCTs located under the dog's skin (subcutaneous), in particular areas of a dog's leg. Stelfonta is injected directly into the MCT. Stelfonta works by activating a protein that spreads throughout the treated tumor, which disintegrates tumor cells.

<span class="mw-page-title-main">Diglyceride</span> Type of fat derived from glycerol and two fatty acids

A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are natural components of food fats, though minor in comparison to triglycerides. DAGs can act as surfactants and are commonly used as emulsifiers in processed foods. DAG-enriched oil has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat; with total annual sales of approximately USD 200 million in Japan since its introduction in the late 1990s till 2009.

References

  1. ↑ "[(1R,2R,6S,7S,8R,10S,11S,12R,14S,16S,17R,18R)-6,7-dihydroxy-8-(hydroxymethyl)-4,18-dimethyl-5-oxo-14-phenyl-16-prop-1-en-2-yl-9,13,15,19-tetraoxahexacyclo[12.4.1.01,11.02,6.08,10.012,16]nonadec-3-en-17-yl] (2E,4E)-5-phenylpenta-2,4-dienoate". pubchem.ncbi.nlm.nih.gov.
  2. 1 2 3 Robertson, John. "The Poison Garden". The Poison Garden website. Robbo Services Ltd. Retrieved 28 March 2013.
  3. ↑ Plants, Practical (12 September 2012). "Practical Plants". Daphne mezereum. Retrieved 28 March 2013.
  4. ↑ "Daphne mezereum - L." Plants For A Future. 2012. Retrieved 28 March 2013.
  5. ↑ "Mezereum Homeopathy Information". Beneforce. Retrieved 28 March 2013.
  6. ↑ Dybedahl, Calle. "Suicide Faq" . Retrieved 27 March 2013.
  7. ↑ Saraiva L.; Fresco, Paula; Pinto, Eugénia; Portugal, Helena; Gonçalves, Jorge (2001). "Differential Activation oby Daphnetoxin and Mezerein of PKC-Isotypes α, βI, δ and ζ". Planta Medica. 67 (9): 787–790. doi:10.1055/s-2001-18843. PMID   11745011. S2CID   260251938.
  8. ↑ Miyake R, Tanaka Y, Tsuda T, Kaibuchi K, Kikkawa U, Nishizuka Y (1984). "Activation of protein kinase C by non-phorbol tumor promoter, mezerein". Biochemical and Biophysical Research Communications. 121 (2): 649–656. doi:10.1016/0006-291X(84)90231-6. PMID   6233978.
  9. ↑ Koenderink, Jan (2013). "Chemical carcinogenesis" (PDF). Retrieved 1 April 2013.[ permanent dead link ]
  10. ↑ Apte, Udayan (2021). "Molecular Mechanisms of Chemical Carcinogenesis" (PDF). Society of Toxicology. Retrieved 1 February 2024.
  11. ↑ Black A, Black J (2013). "Protein kinase C signaling and cell cycle regulation. Review". Front Immunol. 3 (423): 423. doi: 10.3389/fimmu.2012.00423 . PMC   3547298 . PMID   23335926.
  12. ↑ Huynh KM, Soh JW, Dash R, Sarkar D, Fisher PB, Kang D (2010). "FOXM1 Expression Mediates Growth Suppression During Terminal Differentiation of HO-1 Human Metastatic Melanoma Cells". J. Cell. Physiol. 226 (1): 194–204. doi:10.1002/jcp.22326. PMID   20658516. S2CID   206049407.
  13. ↑ Bögi K, Lorenzo PS, Szállázsi Z, Ács P, Wagner GS, Blumberg PM (1998). "Differential Selectivity of Ligands for the Cla and Clb Phorbol Ester Binding Domains of Protein Kinase Co: Possible Correlation with Tumor promoting Activity". Cancer Research. 58 (7): 1423–1428. PMID   9537243.
  14. ↑ Driedger, P & Blumberg, M. (1980). "Structure-Activity Relationships in Chick Embryo Fibroblasts for Phorbol-related Diterpene Esters Showing Anomalous Activities in Vivo". Cancer Research. 40 (40): 339–346. PMID   7356517 . Retrieved 12 March 2013.
  15. ↑ Tsuru; et al. (2002). "Role of PKC isoforms in glucose transport in 3T3-L1 adipocytes: insignificance of atypical PKC". American Journal of Physiology. Endocrinology and Metabolism. 238 (2): 338–345. doi:10.1152/ajpendo.00457.2001. PMID   12110540.
  16. ↑ Lee; Yu, MR; Song, JS; Ha, H; et al. (2004). "Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells". Kidney International. 65 (4): 1170–1179. doi: 10.1111/j.1523-1755.2004.00491.x . PMID   15086456.
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