Abstract
The active components in cloves are eugenol and isoeugenol. Eugenol has recently become a focus of interest because of its potential role in alleviating and preventing chronic diseases such as cancer, inflammatory reactions, and other conditions. The radical-scavenging and anti-inflammatory activities of eugenol have been shown to modulate chronic diseases in vitro and in vivo, but in humans, the therapeutic use of eugenol still remains to be explored. Based on a review of the recent literature, the antioxidant, anti-proliferative, and anti-inflammatory activities of eugenol and its related compounds are discussed in relation to experimentally determined antioxidant activity (stoichiometric factor n and inhibition rate constant) and theoretical parameters [phenolic O–H bond dissociation enthalpy (BDE), ionization potential (IP according to Koopman’s theorem), and electrophilicity (ω)], calculated using a density functional theory method. Dimers of eugenol and its related compounds showed large antioxidant activities and high ω values and also exerted efficient anti-inflammatory activities. Eugenol appears to possess multiple antioxidant activities (dimerization, recycling, and chelating effect) in one molecule, thus having the potential to alleviate and prevent chronic diseases.
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Cortés-Rojas DF, de Souza CR, Oliveira WP (2014) Clove (Syzygium aromaticum): a precious spice. Asian Pac J Trop Biomed 4:90–96. doi:10.1016/S2221-1691(14)60215-X
Prakash P, Gupta N (2005) Therapeutic uses of Ocimum sanctum Linn (Tulsi) with a note on eugenol and its pharmacological actions: a short review. Indian J Physiol Pharmacol 49:125–131
Kadoma Y, Murakami Y, Atsumi T, Ito S, Fujisawa S (2009) Cloves (Eugenol). In: Aggarwal BB, Kunnumakkara AB (eds) Molecular targets and therapeutic uses of species: modern uses for ancient medicine. World Scientific, Singapore, pp 117–148
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616. doi:10.1016/j.freeradbiomed.2010.09.006
Carreras A, Mateos-Martín ML, Velázquez-Palenzuela A, Brillas E, Sánchez-Tena S, Cascante M, Juliá L, Torres JL (2012) Punicalagin and catechins contain polyphenolic substructures that influence cell viability and can be monitored by radical chemosensors sensitive to electron transfer. J Agric Food Chem 60:1659–1665. doi:10.1021/jf204059x
Fujisawa S, Atsumi T, Kadoma Y, Sakagami H (2002) Antioxidant and prooxidant action of eugenol-related compounds and their cytotoxicity. Toxicology 177:39–54
Fujisawa S, Atsumi T, Murakami Y, Kadoma Y (2005) Dimerization, ROS formation and biological activity of o-mrthoxyphenols. Arch Immunol Ther Exp (Warsz) 53:28–38
Kadoma Y, Ito S, Atsumi T, Fujisawa S (2009) Mechanisms of cytotoxicity of 2- or 2,6-di-tert-butylphenols and 2-methoxyphenols in terms of inhibition rate constant and a theoretical parameter. Chemosphere 74:626–632. doi:10.1016/j
Fujisawa S, Kadoma Y (2012) Relationship between phenol-induced cytotoxicity and experimental inhibition rate constant or a theoretical parameter. Mini Rev Med Chem 12:477–490
Murakami Y, Shoji M, Hanazawa S, Tanaka S, Fujisawa S (2003) Preventive effect of bis-eugenol, a eugenol ortho dimer, on lipopolysaccharide-stimulated nuclear factor kappa B activation and inflammatory cytokine expression in macrophages. Biochem Pharmacol 66:1061–1066
Okada N, Hirata A, Murakami Y, Shoji M, Sakagami H, Fujisawa S (2005) Induction of cytotoxicity and apoptosis and inhibition of cyclooxygenase-2 gene expression by eugenol-related compounds. Anticancer Res 25:3263–3269
Atsumi T, Murakami Y, Shibuya K, Tonosaki K, Fujisawa S (2005) Induction of cytotoxicity and apoptosis and inhibition of cyclooxygenase-2 gene expression, by curcumin and its analog, alpha-diisoeugenol. Anticancer Res 25:4029–4036
Atsumi T, Fujisawa S, Tonosaki K (2005) A comparative study of the antioxidant/prooxidant activities of eugenol and isoeugenol with various concentrations and oxidation conditions. Toxcol In Vitro 19:1024–1033. doi:10.1016/j.tiv.2005.04.012
Hirata A, Murakami Y, Atsumi T, Shoji M, Ogiwara T, Shibuya K, Ito S, Yokoe I, Fujisawa S (2005) Ferulic acid dimer inhibits lipopolysaccharide-stimulated cyclooxygenase-2 expression in macrophages. In Vivo 19:849–853
Hirata A, Murakami Y, Shoji M, Kadoma Y, Fujisawa S (2005) Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory a ctivity on COX-2 expression. Anticancer Res 25:3367–3374
Murakami Y, Shoji M, Hirata A, Tanaka S, Yokoe I, Fujisawa S (2005) Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages. Arch Biochem Biophys 434:326–332
Murakami Y, Shoji M, Hirata A, Tanaka S, Hanazawa S, Yokoe I, Fujisawa S (2006) An ortho dimer of butylated hydroxyanisole inhibits nuclear factor kappa B activation and gene expression of inflammatory cytokines in macrophages stimulated by Porphyromonas gingivalis fimbriae. Arch Biochem Biophys 449:171–177
Murakami Y, Shoji M, Ogiwara T, Tanaka S, Yokoe I, Fujisawa S (2006) Preventive effect of ortho dimer of butylated hydroxyanisole on activator protein-1 activation and cyclooxygenase-2 expression in macrophages stimulated by fimbriae of Porphyromonas gingivalis, an oral anaerobe. Anticancer Res 26:2915–2920
Hirata A (2006) Inhibitory effects of ortho-methoxyphenol-related compounds on lipopolysaccharide-stimulated cyclooxygenase-2 expression in macrophages. J Meikai Dent Med 35:42–52 (Japanese)
Murakami Y, Hirata A, Ito S, Shoji M, Tanaka S, Yasui T, Machino M, Fujisawa S (2007) Re-evaluation of cyclooxygenase-2-inhibiting activity of vanillin and guaiacol in macrophages stimulated with lipopolysaccharide. Anticancer Res 27:801–807
Murakami Y, Ishii H, Takada N, Tanaka S, Machino M, Ito S, Fujisawa S (2008) Comparative anti-inflammatory activities of curcumin and tetrahydrocurcumin based on the phenolic O–H bond dissociation enthalpy, ionization potential and quantum chemical descriptor. Anticancer Res 28:699–707
Murakami Y, Ishii H, Hoshina S, Takada N, Ueki A, Tanaka S, Kadoma Y, Ito S, Machino M, Fujisawa S (2009) Antioxidant and cyclooxygenase-2-inhibiting activity of 4,4′-biphenol, 2,2′-biphenol and phenol. Anticancer Res 9:2403–2410
Murakami Y, Kawata A, Seki Y, Koh T, Yuhara K, Maruyama T, Machino M, Ito S, Kadoma Y, Fujisawa S (2012) Comparative inhibitory effects of magnolol, honokiol, eugenol and bis-eugenol on cyclooxygenase-2 expression and nuclear factor-kappa B activation in RAW264.7 macrophage-like cells stimulated with fimbriae of Porphyromonas gingivalis. In Vivo 26:941–950
Murakami Y, Kawata A, Ito S, Katayama T, Fujisawa S (2014). Inhibitory of p-cresol and p-hydroxy anisole dimers on expression of the cyclooxygenase-2 gene and lipopolysaccharide-stimulated activation of nuclear factor-κB in RAW264.7 cells. In Vivo 28:719–725
Fujisawa S, Kadoma Y, Masuhara E (1987) A calorimetric study of the interaction of synthetic phospholipid liposomes with lipid-soluble small molecules used as dental materials and devices. Biomed Mater Res 21:89–98
Fujisawa S, Kadoma Y, Komoda Y (1988) 1H and 13C NMR studies of the interaction of eugenol, phenol, and triethyleneglycol dimethacrylate with phospholipid liposomes as a model system for odontoblast membranes. J Dent Res 67:1438–1441
Nagababu E, Lakshmaiah N (1994) Inhibition of microsomal lipid peroxidation and monooxygenase activities by eugenol. Free Radic Res 20:253–266
Fujisawa S, Masuhara E (1981) Binding of eugenol and o-ethoxybenzoic acid to bovine serum albumin. J Dent Res 60:860–864
Thompson D, Norbeck K, Olsson LI, Constantin-Teodosiu D, Van der Zee J, Moldéus P (1989) Peroxidase-catalyzed oxidation of eugenol: formation of a cytotoxic metabolite(s). J Biol Chem 264:1016–1021
Bondet V, Brand-Williams W, Berset C (1997) Mechanism of antioxidant activity using DPPH. free radical method. Lebensm-Wiss u-Technol 30:609–615
Fischer IU, von Unruh GE, Dengler HJ (1990) The metabolism of eugenol in man. Xenobiotica 20:209–222
Burton GW, Ingold KU (1984) beta-Carotene: an unusual type of lipid antioxidant. Science 224:569–573
Pryor WA, Stricland T, Church DF (1988) Comparison of the efficiency of several natural and synthetic antioxidants in aqueous sodium dodecyl sulfate micelle solutions. J Am Chem Soc 110:2224–2229. doi:10.1021/ja00215a036
Horswill EC, Howard JA, Ingold KU (1966) The oxidation of phenol. III. The stoichiometries for the oxidation of some substituted phenols with peroxy radicals. Can J Chem 44:985–991
Simmons KE, Minard RD, Bollag JM (1988) Oxidative coupling and polymerization of guaiacol, a lignin derivative. Soil Sci Soc Am J 52:1356–1360. doi:10.2136/sssaj1988.03615995005200050028x
Zhang H-Y (2005) Structure-activity relationships and rational design strategies for radical-scavenging antioxidants. Curr Comput Aided Drug Des 1:257–273. doi:10.2174/1573409054367691
Amorati R, Ferroni F, Pedulli GF, Valgimigli L (2003) Modeling the co-antioxidant behavior of monofunctional phenols. Applications to some relevant compounds. J Org Chem 68:9654–9658. doi:10.1021/jo0351825.14656091
Cheng Z, Ren J, Yan G, Li Y, Chang W, Chen Z (2003) Quantitative elucidation of the molecular mechanisms of hydroxyl radical quenching reactivity of phenolic compounds. Bioorg Chem 31:149–162
Ogata M, Hoshi M, Urano S, Endo T (2000) Antioxidant activity of eugenol and related monomeric and dimeric compounds. Chem Pharm Bull (Tokyo) 48:1467–1469
Di Carlo M, Giacomazza D, Picone P, Nuzzo D, San Biagio PL (2012) Are oxidative stress and mitochondrial dysfunction the key players in the neurodegerative diseases? Free Radic Res 46:1327–1338. doi:10.3109/10715762.2012.714466
Yoo CB, Han KT, Cho KS, Ha J, Park HJ, Nam JH, Kil UH, Lee KT (2005) Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukemia cells. Cancer Lett 225:41–52
Pisano M, Pagnan G, Loi M, Mura ME, Tilocca GM, Palmieri G, Fabbri D, Dettori MA, Delogu G, Ponzoni M, Rozzo C (2007) Antiproliferative and pro-apoptotic activity of eugenol-related biphenyls on malignant melanoma cells. Mol Cancer 6:8. doi:10.1186/1476-4598-6-8
Ghosh R, Nadiminty N, Fitzpatrick JE, Alworth WL, Slaga TJ, Kumar AP (2005) Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. J Biol Chem 280:5812–5819
Koh T, Murakami Y, Tanaka S, Machino M, Sakagami H (2013) Re-evaluation of anti-inflammatory potential of eugenol in IL-1β-stimulated gingival fibroblast and pulp cells. In Vivo 27:269–273
Koh T, Murakami Y, Tanaka S, Machino M, Onuma H, Kaneko M, Sugimoto M, Soga T, Tomita M, Sakagami H (2013) Changes of metabolic profiles in an oral squamous cell carcinoma cell line induced by eugenol. In Vivo 27:233–243
Manikandan P, Vinothini G, Vidya Priyadarsini R, Prathiba D, Nagini S (2011) Eugenol inhibits cell proliferation via NF-κB suppression in a rat model of gastric carcinogenesis induced by MNNG. Invest New Drugs 29:110–117. doi:10.1007/s10637-009-9345-2
Wright JS, Erin R. Johnson ER, DiLabio GA (2001) Predicting the activity of phenolic antioxidants: theoretical method, analysis of substituent effects, and application to major families of antioxidants. J Am Chem Soc 123:1173–1183. doi:10.1021/ja002455u
Selassie CD, DeSoyza TV, Rosario M, Gao H, Hansch C (1998) Phenol toxicity in leukemia cells: a radical process? Chem Biol Interact 113:175–190. doi:10.1016/S0009-2797(98)00027-1
Yao JC, Duan WG, Yun Y, de Liu Q, Yan M, Jiang ZZ, Zhang LY (2007) Screening method for nonsteroidal antiinflammatory drugs based on the cyclooxygenase 2 pathway activated by serum-free stimulation in A549 cells. Yakugaku Zasshi 127:527–532
Kelm MA, Nair MG, Strasburg GM, DeWitt DL (2000) Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomedicine 7–13
Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB (2006) Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 69:195–206
Murakami Y, Kawata A, Ito S, Katayama T, Fujisawa S (2015) The radical scavenging activity and cytotoxicity of resveratrol, orcinol and 4-allylphenol and their inhibitory effects on Cox-2 gene expression and Nf-κB activation in RAW264.7 cells stimulated with Porphyromonas gingivalis-fimbriae. In Vivo 29:341–349
Lee J, Jung E, Park J, Jung K, Lee S, Hong S, Park J, Park E, Kim J, Park S, Park D (2005) Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling. Planta Med 71:338–343
Sgarbossa A, Giacomazza D, di Carlo M (2015) Ferulic acid: a hope for Alzheimer’s disease therapy from plants. Nutrients 5764–5782. doi:10.3390/nu7075246
Putz MV, Ionaşcu C, Putz AM, Ostafe V (2011) Alert-QSAR. Implications for electrophilic theory of chemical carcinogenesis. Int J Mol Sci 12:5098–5134
Enoch SJ, Madden JC, Cronin MT (2008) Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach. SAR QSAR Environ Res 19:555–578. doi:10.1080/10629360802348985
LoPachin RM, Barber DS, Gavin T (2008) Molecular mechanisms of the conjugated alpha, beta-unsaturated carbonyl derivatives: relevance to neurotoxicity and neurodegenerative diseases. Toxicol Sci 104:235–249
Chapple IL (1996) Role of free radicals and antioxidants in the pathogenesis of inflammatory periodontal diseases. Clin Mol Pathol 49:247–255
Deepak V, Kasonga A, Kruger MC, Coetzee M (2015) Inhibitory effects of eugenol on RANKL-induced osteoclast formation via attenuation of NF-κB and MAPK pathways. Connect Tissue Res 56:195–203. doi:10.3109/03008207.2014.989320
Jaganathan SK, Supriyanto E (2012) Antiproliferative and molecular mechanism of eugenol-induced apoptosis in cancer cells. Molecules 17:6290–6304. doi:10.3390/molecules17066290
Kaur G, Athar M, Alam MS (2010) Eugenol precludes cutaneous chemical carcinogenesis in mouse by preventing oxidative stress and inflammation and by inducing apoptosis. Mol Carcinog 49:290–301. doi:10.1002/mc.20601
Yogalakshmi B, Viswanathan P, Anuradha CV (2010) Investigation of antioxidant, anti-inflammatory and DNA-protective properties of eugenol in thioacetamide-induced liver injury in rats. Toxicology 268:204–212. doi:10.1016/j.tox.2009.12.018
Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283:65–87. doi:10.1016/j.tox.2011.03.001
Jeong KJ, Kim do Y, Quan HY, Jo HK, Kim GW, Chung SH (2014) Effects of eugenol on hepatic glucose production and AMPK signaling pathway in hepatocytes and C57BL/6 J mice. Fitoterapia 93:150–162. doi:10.1016/j.fitote.2013.12.023
Saptarini NM, Saputri FA, Levita J (2014) Molecular modeling study of PPARr agonists: dehydro-di-isoeugenol, macelignan, pioglitazone, netoglitazone, and rosiglitazone as antidiabetic. Inter J Chem 6. http://dx.doi.org/10.5539/ijc.v6n2p48
Willson TM, Brown PJ, Sternbach DD, Henke BR (2000) The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527–550
Chami N, Chami F, Bennis S, Trouillas J, Remmal A (2004) Antifungal treatment with carvacrol and eugenol of oral candidiasis in immunosuppressed rats. Braz J Infect Dis 8:217–226
Chami F, Chami N, Bennis S, Trouillas J, Remmal A (2004) Evaluation of carvacrol and eugenol as prophylaxis and treatment of vaginal candidiasis in an immunosuppressed rat model. J Antimicrob Chemother 54:909–914
Natsch A, Haupt T (2013) Utility of rat liver S9 fractions to study skin-sensitizing prohaptens in a modified KeratinoSens assay. Toxicol Sci 135:356–368. doi:10.1093/toxsci/kft160
Mahadlek J, Charoenteeraboon J, Phaechamud T (2010) Zinc Oxide Gels for periodontitis treatment. J Metal Mater Mineral 20:159–163
Tanaka S, Royds C, Buckley D, Basketter DA, Goossens A, Bruze M, Svedman C, Menné T, Johansen JD, White IR, McFadden JP (2004) Contact allergy to isoeugenol and its derivatives: problems with allergen substitution. Contact Dermatitis 51:288–291
Takeyoshi M, Iida K, Suzuki K, Yamazaki S (2008) Skin sensitization potency of isoeugenol and its dimers evaluated by a non-radioisotopic modification of the local lymph node assay and guinea pig maximization test. J Appl Toxicol 28:530–534
Rastogi SC, Johansen JD (2008) Significant exposures to isoeugenol derivatives in perfumes. Contact Dermatitis 58:278–281. doi:10.1111/j.1600-0536.2007.01283.x
Karlberg AT, Bergström MA, Börje A, Luthman K, Nilsson JL (2008) Allergic contact dermatitis–formation, structural requirements, and reactivity of skin sensitizers. Chem Res Toxicol 21:53–69
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We are grateful to Toshiko Atsumi, Mariko Ishihara, Hiroshi Sakagami, Yoshinori Kadoma and Shigeru Ito for their valuable support.
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Fujisawa, S., Murakami, Y. (2016). Eugenol and Its Role in Chronic Diseases. In: Gupta, S., Prasad, S., Aggarwal, B. (eds) Drug Discovery from Mother Nature. Advances in Experimental Medicine and Biology, vol 929. Springer, Cham. https://doi.org/10.1007/978-3-319-41342-6_3
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