Chemistry:Arachidonate 5-lipoxygenase inhibitor

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Arachidonate 5-lipoxygenase inhibitors are compounds that slow or stop the action of the arachidonate 5-lipoxygenase (5-lipoxygenase or 5-LOX) enzyme, which is responsible for the production of inflammatory leukotrienes. The overproduction of leukotrienes is a major cause of inflammation in asthma, allergic rhinitis, and osteoarthritis.[1][2] Examples of 5-LOX inhibitors include the pharmaceutical drugs meclofenamate sodium, zileuton[3][4] and the natural products myxochelins/pseudochelin[5][6] as well as nordihydroguaiaretic acid (NDGA).[7]

Some chemicals found in trace amounts in food, as well as some dietary supplements, have been shown to inhibit 5-LOX; these include baicalein, caffeic acid, curcumin,[3] hyperforin and St John's wort.[8][9][10]

Acetyl-keto-beta-boswellic acid (AKBA), one of the bioactive boswellic acids found in Boswellia serrata (Indian Frankincense) has been found to inhibit 5-lipoxygenase strongly as an allosteric inhibitor.[7] Boswellia administration has been shown to reduce brain edema in patients irradiated for brain tumor and it's believed to be due to 5-lipoxygenase inhibition.[11][12]

See also

References

  1. ↑ David L. Nelson, Michael M. Cox. Lehninger's Principles of Biochemistry, Fifth Edition. W.H. Freeman and Co., 2008, p. 359.
  2. ↑ Laufer, S (2003). "Role of eicosanoids in structural degradation in osteoarthritis". Curr Opin Rheumatol 15 (5): 623–627. doi:10.1097/00002281-200309000-00017. PMID 12960491. 
  3. ↑ 3.0 3.1 "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochim. Biophys. Sin. (Shanghai) 45 (9): 709–719. September 2013. doi:10.1093/abbs/gmt064. PMID 23752617. 
  4. ↑ "Zyflo (Zileuton tablets)". Cornerstone Therapeutics Inc.. June 2012. p. 1. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020471s017lbl.pdf. "Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the (R)-(+)- and (S)-(-)-enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients." 
  5. ↑ Schieferdecker, Sebastian; König, Stefanie; Koeberle, Andreas; Dahse, Hans-Martin; Werz, Oliver; Nett, Markus (2015-02-27). "Myxochelins Target Human 5-Lipoxygenase" (in en). Journal of Natural Products 78 (2): 335–338. doi:10.1021/np500909b. ISSN 0163-3864. PMID 25686392. https://pubs.acs.org/doi/10.1021/np500909b. 
  6. ↑ Sester, Angela; Winand, Lea; Pace, Simona; Hiller, Wolf; Werz, Oliver; Nett, Markus (2019-09-27). "Myxochelin- and Pseudochelin-Derived Lipoxygenase Inhibitors from a Genetically Engineered Myxococcus xanthus Strain" (in en). Journal of Natural Products 82 (9): 2544–2549. doi:10.1021/acs.jnatprod.9b00403. ISSN 0163-3864. PMID 31465225. https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00403. 
  7. ↑ 7.0 7.1 Gilbert, Nathaniel C.; Gerstmeier, Jana; Schexnaydre, Erin E.; Börner, Friedemann; Garscha, Ulrike; Neau, David B.; Werz, Oliver; Newcomer, Marcia E. (July 2020). "Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products" (in en). Nature Chemical Biology 16 (7): 783–790. doi:10.1038/s41589-020-0544-7. ISSN 1552-4450. PMID 32393899. 
  8. ↑ "Hyperforin". Hyperforin. University of Alberta. 30 June 2013. "Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions". 
    "Inhibition of prostaglandin E(2) production by anti-inflammatory hypericum perforatum extracts and constituents in RAW264.7 Mouse Macrophage Cells". J Agric Food Chem 55 (18): 7323–31. 2007. doi:10.1021/jf0710074. PMID 17696442. 
    "In-vitro antitumor activity evaluation of hyperforin derivatives". J Asian Nat Prod Res 13 (8): 688–99. 2011. doi:10.1080/10286020.2011.584532. PMID 21751836. 
    Hübner AT (2003). "Treatment with Hypericum perforatum L. does not trigger decreased resistance in Staphylococcus aureus against antibiotics and hyperforin". Phytomedicine 10 (2–3): 206–8. doi:10.1078/094471103321659951. PMID 12725578. 
    "Antidepressant activity of hyperforin conjugates of the St. John's wort, Hypericum perforatum Linn.: an experimental study". Indian J Exp Biol 39 (12): 1302–4. 2001. PMID 12018529. 
    1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
    2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity
  9. ↑ "A systematic review for anti-inflammatory property of clusiaceae family: a preclinical approach". Evid Based Complement Alternat Med 2014: 960258. 2014. doi:10.1155/2014/960258. PMID 24976853. "These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity.". 
  10. ↑ "Topical application of St. John's wort (Hypericum perforatum)". Planta Med. 80 (2–3): 109–20. February 2014. doi:10.1055/s-0033-1351019. PMID 24214835. "Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 μmol/L and 1.2 μmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 μmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.". 
  11. ↑ Simon Kirste (2009). Antiödematöse Wirkung von Boswellia serrata auf dasStrahlentherapie - assoziierte Hirnödem (MD thesis). Albert-Ludwigs-Universität Freiburg im Breisgau – via Deutsche National Bibliothek.
  12. ↑ "Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial.". Cancer 117 (16): 3788–95. 2011. doi:10.1002/cncr.25945. PMID 21287538. 

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