The Bioactivity and Toxicological Actions of Carvacrol

REFERENCES

• Aeschbach, R., Loliger, J., Scott, B.C., Murcia, A., Butler, J., Halliwell, B. and Aruoma, O.I. (1994). Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol. Food Chem. Toxicol. 32:31–36.
   PubMed Web of Science ®Google Scholar
• Ahmad, A., Khan, A., Akhtar, F., Yousuf, S., Xess, I., Khan, L.A. and Manzoor, N. (2011). Fungicidal activity of thymol and carvacrol by disrupting ergosterol biosynthesis and membrane integrity against Candida. Eur. J. Clin. Microbiol. Infect. Dis. 30:41–50.
   PubMed Web of Science ®Google Scholar
• Alma, M.H., Mavi, A., Yildirim, A., Digrak, M. and Hirata, T. (2003). Screening chemical composition and in vitro antioxidant and antimicrobial activities of the essential oils from Origanum syriacum L. growing in Turkey. Biol. Pharm. Bull. 26:1725–1729.
   PubMed Web of Science ®Google Scholar
• Andersen, A. (2006). Final report on the safety assessment of sodium p-chloro-m-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol. Int. J. Toxicol. 25(Suppl 1):29–127.
   PubMedGoogle Scholar
• Aristatile, B., Al-Numair, K.S., Al-Assaf, A.H. and Pugalendi, K.V. (2011). Pharmacological effect of carvacrol on D: -galactosamine-induced mitochondrial enzymes and DNA damage by single-cell gel electrophoresis. J. Nat. Med. 65:568–577.
   PubMed Web of Science ®Google Scholar
• Aristatile, B., Al-Numair, K.S., Veeramani, C. and Pugalendi, K.V. (2009a). Antihyperlipidemic effect of carvacrol on D-galactosamine-induced hepatotoxic rats. J. Basic. Clin. Physiol. Pharmacol. 20:15–27.
   PubMedGoogle Scholar
• Aristatile, B., Al-Numair, K.S., Veeramani, C. and Pugalendi, K.V. (2009b). Effect of carvacrol on hepatic marker enzymes and antioxidant status in D-galactosamine-induced hepatotoxicity in rats. Fundam. Clin. Pharmacol. 23:757–765.
   PubMed Web of Science ®Google Scholar
• Arunasree, K.M. (2010). Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231. Phytomedicine 17:581–588.
   PubMed Web of Science ®Google Scholar
• Austgulen, L.T., Solheim, E. and Scheline, R.R. (1987). Metabolism in rats of p-cymene derivatives: carvacrol and thymol. Pharmacol. Toxicol. 61:98–102.
   PubMedGoogle Scholar
• Aydin, S., Basaran, A.A. and Basaran, N. (2005a). The effects of thyme volatiles on the induction of DNA damage by the heterocyclic amine IQ and mitomycin C. Mutat. Res. 581:43–53.
   PubMed Web of Science ®Google Scholar
• Aydin, S., Basaran, A.A. and Basaran, N. (2005b). Modulating effects of thyme and its major ingredients on oxidative DNA damage in human lymphocytes. J. Agric. Food Chem. 53:1299–1305.
   PubMed Web of Science ®Google Scholar
• Barrett-Bee, K. and Dixon, G. (1995). Ergosterol biosynthesis inhibition: a target for antifungal agents. Acta. Biochim. Pol. 42:465–479.
   PubMed Web of Science ®Google Scholar
• Bimczok, D., Rau, H., Sewekow, E., Janczyk, P., Souffrant, W.B. and Rothkotter, H.J. (2008). Influence of carvacrol on proliferation and survival of porcine lymphocytes and intestinal epithelial cells in vitro. Toxicol. In Vitro 22:652–658.
   PubMed Web of Science ®Google Scholar
• Borbiro, I., Lisztes, E., Toth, B.I., Czifra, G., Olah, A., Szollosi, A.G., Szentandrassy, N., Nanasi, P.P., Peter, Z., Paus, R., Kovacs, L. and Biro, T. (2011). Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J. Invest Dermatol. 131:1605–1614.
   PubMed Web of Science ®Google Scholar
• Boskabady, M.H., Jafari, Z. and Pouraboli, I. (2011). The effect of carvacrol on muscarinic receptors of guinea-pig tracheal chains. Phytother. Res. 25:530–535.
   PubMed Web of Science ®Google Scholar
• Boskabady, M.H. and Jandaghi, P. (2003). Relaxant effects of carvacrol on guinea pig tracheal chains and its possible mechanisms. Pharmazie 58:661–663.
   PubMed Web of Science ®Google Scholar
• Burt, S. (2004). Essential oils: their antibacterial properties and potential applications in foods–a review. Int. J. Food. Microbiol. 94:223–253.
   PubMed Web of Science ®Google Scholar
• Canbek, M., Uyanoglu, M., Bayramoglu, G., Senturk, H., Erkasap, N., Koken, T., Uslu, S., Demirustu, C., Aral, E. and Husnu Can Baser, K. (2008). Effects of carvacrol on defects of ischemia-reperfusion in the rat liver. Phytomedicine 15:447–452.
   PubMed Web of Science ®Google Scholar
• Cavalcanti, S.C., Niculau Edos, S., Blank, A.F., Camara, C.A., Araujo, I.N. and Alves, P.B. (2010). Composition and acaricidal activity of Lippia sidoides essential oil against two-spotted spider mite (Tetranychus urticae Koch). Bioresour. Technol. 101:829–832.
   PubMed Web of Science ®Google Scholar
• Cepeda-Valery, B., Pressman, G.S., Figueredo, V.M. and Romero-Corral, A. (2011). Impact of obesity on total and cardiovascular mortality–fat or fiction? Nat. Rev. Cardiol. 8:233–237.
   PubMed Web of Science ®Google Scholar
• Chami, F., Chami, N., Bennis, S., Trouillas, J. and 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.
   PubMed Web of Science ®Google Scholar
• Chami, N., Bennis, S., Chami, F., Aboussekhra, A. and Remmal, A. (2005). Study of anticandidal activity of carvacrol and eugenol in vitro and in vivo. Oral. Microbiol. Immunol. 20:106–111.
   PubMedGoogle Scholar
• Chen, F., Shi, Z., Neoh, K.G. and Kang, E.T. (2009). Antioxidant and antibacterial activities of eugenol and carvacrol-grafted chitosan nanoparticles. Biotechnol. Bioeng. 104:30–39.
   PubMed Web of Science ®Google Scholar
• Cho, S., Choi, Y., Park, S. and Park, T. (2012). Carvacrol prevents diet-induced obesity by modulating gene expressions involved in adipogenesis and inflammation in mice fed with high-fat diet. J. Nutr. Biochem. 23:192–201.
   PubMed Web of Science ®Google Scholar
• Coimbra, M., Isacchi, B., van Bloois, L., Torano, J.S., Ket, A., Wu, X., Broere, F., Metselaar, J.M., Rijcken, C.J., Storm, G., Bilia, R. and Schiffelers, R.M. (2011). Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes. Int. J. Pharm. 416:433–442.
   PubMed Web of Science ®Google Scholar
• Conner, D.E. and Beuchat, L.R. (1984). Sensitivity of heat-stressed yeasts to essential oils of plants. Appl. Environ. Microbiol. 47:229–233.
   PubMed Web of Science ®Google Scholar
• Coujolle, F. and Franck, C. (1944). Comparative toxicity of thymol and carvacrol. Bull. Soc. Chim. Biol. 26:334–342.
   Google Scholar
• Cox, S.D. and Markham, J.L. (2007). Susceptibility and intrinsic tolerance of Pseudomonas aeruginosa to selected plant volatile compounds. J. Appl. Microbiol. 103:930–936.
   PubMed Web of Science ®Google Scholar
• Cristani, M., D’Arrigo, M., Mandalari, G., Castelli, F., Sarpietro, M.G., Micieli, D., Venuti, V., Bisignano, G., Saija, A. and Trombetta, D. (2007). Interaction of four monoterpenes contained in essential oils with model membranes: implications for their antibacterial activity. J. Agric. Food Chem. 55:6300–6308.
   PubMed Web of Science ®Google Scholar
• Cukierman, E. and Khan, D.R. (2010). The benefits and challenges associated with the use of drug delivery systems in cancer therapy. Biochem. Pharmacol. 80:762–770.
   PubMed Web of Science ®Google Scholar
• Dalleau, S., Cateau, E., Berges, T., Berjeaud, J.M. and Imbert, C. (2008). In vitro activity of terpenes against Candida biofilms. Int. J. Antimicrob. Agents. 31:572–576.
   PubMed Web of Science ®Google Scholar
• De Vincenzi, M., Stammati, A., De Vincenzi, A. and Silano, M. (2004). Constituents of aromatic plants: carvacrol. Fitoterapia 75:801–804.
   PubMed Web of Science ®Google Scholar
• de Wildt, S.N., Kearns, G.L., Leeder, J.S. and van den Anker, J.N. (1999). Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin. Pharmacokinet. 36:439–452.
   PubMed Web of Science ®Google Scholar
• Decker, K. and Keppler, D. (1972). Galactosamine induced liver injury. Prog. Liver. Dis. 4:183–199.
   PubMedGoogle Scholar
• Di Pasqua, R., Hoskins, N., Betts, G. and Mauriello, G. (2006). Changes in membrane fatty acids composition of microbial cells induced by addiction of thymol, carvacrol, limonene, cinnamaldehyde, and eugenol in the growing media. J. Agric. Food Chem. 54:2745–2749.
   PubMed Web of Science ®Google Scholar
• Doerner, J.F., Hatt, H. and Ramsey, I.S. (2011). Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis. J. Gen. Physiol. 137:271–288.
   PubMed Web of Science ®Google Scholar
• Dong, R.H., Fang, Z.Z., Zhu, L.L., Liang, S.C., Ge, G.B. and Liu, Z.Y. (2012). Investigation of UDP-glucuronosyltransferases (UGTs) inhibitory properties of carvacrol. Phytother. Res. 26:86–90.
   PubMed Web of Science ®Google Scholar
• Earley, S., Gonzales, A.L. and Garcia, Z.I. (2010). A dietary agonist of transient receptor potential cation channel V3 elicits endothelium-dependent vasodilation. Mol. Pharmacol. 77:612–620.
   PubMed Web of Science ®Google Scholar
• Ellepola, A.N. and Samaranayake, L.P. (1998). The effect of limited exposure to antifungal agents on the germ tube formation of oral Candida albicans. J. Oral. Pathol. Med. 27:213–219.
   PubMed Web of Science ®Google Scholar
• Epstein, W. (2003). The roles and regulation of potassium in bacteria. Prog. Nucleic. Acid. Res. Mol. Biol. 75:293–320.
   PubMed Web of Science ®Google Scholar
• Fehrenbacher, J.C., LoVerme, J., Clarke, W., Hargreaves, K.M., Piomelli, D. and Taylor, B.K. (2009). Rapid pain modulation with nuclear receptor ligands. Brain. Res. Rev. 60:114–124.
   PubMed Web of Science ®Google Scholar
• Ferguson, L.R. (2001). Role of plant polyphenols in genomic stability. Mutat. Res. 475:89–111.
   PubMed Web of Science ®Google Scholar
• Freichel, M. and Flockerzi, V. (2007). Biological functions of TRPs unravelled by spontaneous mutations and transgenic animals. Biochem. Soc. Trans. 35:120–123.
   PubMedGoogle Scholar
• Friedman, M., Henika, P.R. and Mandrell, R.E. (2002). Bactericidal activities of plant essential oils and some of their isolated constituents against Campylobacter jejuni, Escherichia coli, Listeria monocytogenes, and Salmonella enterica. J. Food Prot. 65:1545–1560.
   PubMed Web of Science ®Google Scholar
• Gaysinsky, S., Davidson, P.M., Bruce, B.D. and Weiss, J. (2005). Growth inhibition of Escherichia coli O157:H7 and Listeria monocytogenes by carvacrol and eugenol encapsulated in surfactant micelles. J. Food Prot. 68:2559–2566.
   PubMed Web of Science ®Google Scholar
• Gill, A.O. and Holley, R.A. (2006). Disruption of Escherichia coli, Listeria monocytogenes and Lactobacillus sakei cellular membranes by plant oil aromatics. Int. J. Food Microbiol. 108:1–9.
   PubMed Web of Science ®Google Scholar
• Gozzi, C., Convard, A. and Husset, M. (2009). Heterogeneous acid-catalysed isomerization of carvone to carvacrol. React. Kinet. Catal. Lett. 97:301–306.
   Google Scholar
• Griffin, S.G., Wyllie, S.G., Markham, J.L. and Leach, D.N. (1999). The role of structure and molecular properties of terpenoids in determining their antimicrobial activity. Flavour. Frag. J. 14:322–332.
   Web of Science ®Google Scholar
• Guarda, A., Rubilar, J.F., Miltz, J. and Galotto, M.J. (2011). The antimicrobial activity of microencapsulated thymol and carvacrol. Int. J. Food. Microbiol. 146:144–150.
   PubMed Web of Science ®Google Scholar
• Guillen, F., Zapata, P.J., Martinez-Romero, D., Castillo, S., Serrano, M. and Valero, D. (2007). Improvement of the overall quality of table grapes stored under modified atmosphere packaging in combination with natural antimicrobial compounds. J. Food Sci. 72:S185–190.
   PubMed Web of Science ®Google Scholar
• Guimaraes, A.G., Oliveira, G.F., Melo, M.S., Cavalcanti, S.C., Antoniolli, A.R., Bonjardim, L.R., Silva, F.A., Santos, J.P., Rocha, R.F., Moreira, J.C., Araujo, A.A., Gelain, D.P. and Quintans-Junior, L.J. (2010). Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. Basic. Clin. Pharmacol. Toxicol. 107:949–957.
   PubMed Web of Science ®Google Scholar
• Guimaraes, A.G., Xavier, M.A., de Santana, M.T., Camargo, E.A., Santos, C.A., Brito, F.A., Barreto, E.O., Cavalcanti, S.C., Antoniolli, A.R., Oliveira, R.C. and Quintans-Junior, L.J. (2011). Carvacrol attenuates mechanical hypernociception and inflammatory response. Naunyn. Schmiedebergs Arch. Pharmacol.
   Web of Science ®Google Scholar
• Hagan, E.C., Hansen, W.H., Fitzhugh, O.G., Jenner, P.M., Jones, W.I., Taylor, J.M., Long, E.L., Nelson, A.A. and Brouwer, J.B. (1967). Food flavourings and compounds of related structure. II. Subacute and chronic toxicity. Food Cosmet. Toxicol. 5:141–157.
   PubMedGoogle Scholar
• He, L., Mo, H., Hadisusilo, S., Qureshi, A.A. and Elson, C.E. (1997). Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J. Nutr. 127:668–674.
   PubMed Web of Science ®Google Scholar
• Hoiby, N., Ciofu, O., Johansen, H.K., Song, Z.J., Moser, C., Jensen, P.O., Molin, S., Givskov, M., Tolker-Nielsen, T. and Bjarnsholt, T. (2011). The clinical impact of bacterial biofilms. Int. J. Oral. Sci. 3:55–65.
   PubMed Web of Science ®Google Scholar
• Horvathova, E., Turcaniova, V. and Slamenova, D. (2007). Comparative study of DNA-damaging and DNA-protective effects of selected components of essential plant oils in human leukemic cells K562. Neoplasma 54:478–483.
   PubMed Web of Science ®Google Scholar
• Hotta, M., Nakata, R., Katsukawa, M., Hori, K., Takahashi, S. and Inoue, H. (2010). Carvacrol, a component of thyme oil, activates PPARalpha and gamma and suppresses COX-2 expression. J. Lipid. Res. 51:132–139.
   PubMed Web of Science ®Google Scholar
• Iannitelli, A., Grande, R., Di Stefano, A., Di Giulio, M., Sozio, P., Bessa, L.J., Laserra, S., Paolini, C., Protasi, F. and Cellini, L. (2011). Potential antibacterial activity of carvacrol-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles against microbial biofilm. Int. J. Mol. Sci. 12:5039–5051.
   PubMed Web of Science ®Google Scholar
• Ipek, E., Tuylu, B.A. and Zeytinoglu, H. (2003). Effects of carvacrol on sister chromatid exchanges in human lymphocyte cultures. Cytotechnology 43:145–148.
   PubMed Web of Science ®Google Scholar
• Jayakumar, S., Madankumar, A., Asokkumar, S., Raghunandhakumar, S., Gokula Dhas, K., Kamaraj, S., Josephine Divya, M.G. and Devaki, T. (2012). Potential preventive effect of carvacrol against diethylnitrosamine-induced hepatocellular carcinoma in rats. Mol. Cell. Biochem. 360:51–60.
   PubMed Web of Science ®Google Scholar
• Johny, A.K., Hoagland, T. and Venkitanarayanan, K. (2010). Effect of subinhibitory concentrations of plant-derived molecules in increasing the sensitivity of multidrug-resistant Salmonella enterica serovar Typhimurium DT104 to antibiotics. Foodborne. Pathog. Dis. 7:1165–1170.
   PubMed Web of Science ®Google Scholar
• Jukic, M., Politeo, O., Maksimovic, M. and Milos, M. (2007). In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone. Phytother. Res. 21:259–261.
   PubMed Web of Science ®Google Scholar
• Jung, C.H., Ro, S.-H., Cao, J., Otto, N.M. and Kim, D.-H. (2010). mTOR regulation of autophagy. FEBS Lett. 584:1287–1295.
   PubMed Web of Science ®Google Scholar
• Kararli, T.T., Kirchhoff, C.F. and Penzotti, S.C. (1995). Enhancement of transdermal transport of azidothymidine (AZT) with novel terpene and terpene-like enhancers: In vivo-in vitro correlations. J. Control. Rel. 34:43–51.
   Web of Science ®Google Scholar
• Karioti, A., Vrahimi-Hadjilouca, T., Droushiotis, D., Rancic, A., Hadjipavlou-Litina, D. and Skaltsa, H. (2006). Analysis of the essential oil of Origanum dubium growing wild in Cyprus. Investigation of its antioxidant capacity and antimicrobial activity. Planta. Med. 72:1330–1334.
   PubMed Web of Science ®Google Scholar
• Karkabounas, S., Kostoula, O.K., Daskalou, T., Veltsistas, P., Karamouzis, M., Zelovitis, I., Metsios, A., Lekkas, P., Evangelou, A.M., Kotsis, N. and Skoufos, I. (2006). Anticarcinogenic and antiplatelet effects of carvacrol. Exp. Oncol. 28:121–125.
   PubMedGoogle Scholar
• Keawchaoon, L. and Yoksan, R. (2011). Preparation, characterization and in vitro release study of carvacrol-loaded chitosan nanoparticles. Colloid. Surf B Biointerfaces 84:163–171.
   PubMed Web of Science ®Google Scholar
• Kim, S., Jin, Y., Choi, Y. and Park, T. (2011). Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem. Pharmacol. 81:1343–1351.
   PubMed Web of Science ®Google Scholar
• Kisko, G. and Roller, S. (2005). Carvacrol and p-cymene inactivate Escherichia coli O157:H7 in apple juice. BMC Microbiol. 5:36.
   PubMed Web of Science ®Google Scholar
• Knowles, J. and Roller, S. (2001). Efficacy of chitosan, carvacrol, and a hydrogen peroxide-based biocide against foodborne microorganisms in suspension and adhered to stainless steel. J. Food Prot. 64:1542–1548.
   PubMed Web of Science ®Google Scholar
• Knowles, J.R., Roller, S., Murray, D.B. and Naidu, A.S. (2005). Antimicrobial action of carvacrol at different stages of dual-species biofilm development by Staphylococcus aureus and Salmonella enterica serovar Typhimurium. Appl. Environ. Microbiol. 71:797–803.
   PubMed Web of Science ®Google Scholar
• Kong, J.O., Park, I.K., Choi, K.S., Shin, S.C. and Ahn, Y.J. (2007). Nematicidal and propagation activities of thyme red and white oil compounds toward Bursaphelenchus xylophilus (Nematoda: Parasitaphelenchidae). J. Nematol. 39:237–242.
   PubMed Web of Science ®Google Scholar
• Koopman, W.J., Nijtmans, L.G., Dieteren, C.E., Roestenberg, P., Valsecchi, F., Smeitink, J.A. and Willems, P.H. (2010). Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation. Antioxid Redox Signal 12:1431–1470.
   PubMed Web of Science ®Google Scholar
• Koparal, A.T. and Zeytinoglu, M. (2003). Effects of carvacrol on a human non-small cell lung cancer (NSCLC) cell line, A549. Cytotechnology 43:149–154.
   PubMed Web of Science ®Google Scholar
• Kulkarni, S.B., Betageri, G.V. and Singh, M. (1995). Factors affecting microencapsulation of drugs in liposomes. J. Microencapsul 12:229–246.
   PubMed Web of Science ®Google Scholar
• Kunta, J.R., Goskonda, V.R., Brotherton, H.O., Khan, M.A. and Reddy, I.K. (1997). Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J. Pharm. Sci. 86:1369–1373.
   PubMed Web of Science ®Google Scholar
• Lambert, R.J., Skandamis, P.N., Coote, P.J. and Nychas, G.J. (2001). A study of the minimum inhibitory concentration and mode of action of oregano essential oil, thymol and carvacrol. J. Appl. Microbiol. 91:453–462.
   PubMed Web of Science ®Google Scholar
• Lampronti, I., Saab, A.M. and Gambari, R. (2006). Antiproliferative activity of essential oils derived from plants belonging to the Magnoliophyta division. Int. J. Oncol. 29:989–995.
   PubMed Web of Science ®Google Scholar
• Landa, P., Kokoska, L., Pribylova, M., Vanek, T. and Marsik, P. (2009). In vitro anti-inflammatory activity of carvacrol: Inhibitory effect on COX-2 catalyzed prostaglandin E(2) biosynthesis. Arch. Pharm. Res. 32:75–78.
   PubMed Web of Science ®Google Scholar
• Lauridsen, E. (1997). Quality control of essential drugs. Lancet 350:1106–1107.
   PubMed Web of Science ®Google Scholar
• Le Guellec, C., Lacarelle, B., Villard, P.H., Point, H., Catalin, J. and Durand, A. (1995). Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs. Anesth Analg 81:855–861.
   PubMed Web of Science ®Google Scholar
• LeBlanc, B.W., Boue, S., De-Grandi Hoffman, G., Deeby, T., McCready, H. and Loeffelmann, K. (2008). Beta-cyclodextrins as carriers of monoterpenes into the hemolymph of the honey bee (Apis mellifera) for integrated pest management. J. Agric. Food Chem. 56:8565–8573.
   PubMed Web of Science ®Google Scholar
• Lee, J., Jung, E., Yu, H., Kim, Y., Ha, J., Kim, Y.S. and Park, D. (2008). Mechanisms of carvacrol-induced expression of type I collagen gene. J. Dermatol. Sci. 52:160–169.
   PubMed Web of Science ®Google Scholar
• Lee, S.Y. and Jin, H.H. (2008). Inhibitory activity of natural antimicrobial compounds alone or in combination with nisin against Enterobacter sakazakii. Lett. Appl. Microbiol. 47:315–321.
   PubMed Web of Science ®Google Scholar
• Lei, J., Leser, M. and Enan, E. (2010). Nematicidal activity of two monoterpenoids and SER-2 tyramine receptor of Caenorhabditis elegans. Biochem. Pharmacol. 79:1062–1071.
   PubMed Web of Science ®Google Scholar
• Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., Melendez, J.A. and Robinson, J.P. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J. Biol. Chem. 278:8516–8525.
   PubMed Web of Science ®Google Scholar
• Liolios, C.C., Gortzi, O., Lalas, S., Tsaknis, J. and Chinou, I. (2009). Liposomal incorporation of carvacrol and thymol isolated from the essential oil of Origanum dictamnus L. and in vitro antimicrobial activity. Food Chem. 112:77–83.
   Web of Science ®Google Scholar
• Liolios, C.C., Graikou, K., Skaltsa, E. and Chinou, I. (2010). Dittany of Crete: a botanical and ethnopharmacological review. J. Ethnopharmacol. 131:229–241.
   PubMed Web of Science ®Google Scholar
• Lopez-Malo, A., Maris Alzamora, S. and Palou, E. (2005). Aspergillus flavus growth in the presence of chemical preservatives and naturally occurring antimicrobial compounds. Int. J. Food Microbiol. 99:119–128.
   PubMed Web of Science ®Google Scholar
• Lu, Y. and Wu, C. (2010). Reduction of Salmonella enterica contamination on grape tomatoes by washing with thyme oil, thymol, and carvacrol as compared with chlorine treatment. J. Food Prot. 73:2270–2275.
   PubMed Web of Science ®Google Scholar
• Luna, A., Labaque, M.C., Zygadlo, J.A. and Marin, R.H. (2010). Effects of thymol and carvacrol feed supplementation on lipid oxidation in broiler meat. Poult. Sci. 89:366–370.
   PubMed Web of Science ®Google Scholar
• Maeda, T. and Kishioka, S. (2009). Chapter 13 PPAR and Pain. Int. Rev. Neurobiol. 85:165–177.
   PubMed Web of Science ®Google Scholar
• Magyar, J., Szentandrássy, N., Bányász, T., Fülöp, L., Varró, A. and Nánási, P.P. (2004). Effects of terpenoid phenol derivatives on calcium current in canine and human ventricular cardiomyocytes. Eur. J. Pharmacol. 487:29–36.
   PubMed Web of Science ®Google Scholar
• Manabe, A., Nakayama, S. and Sakamoto, K. (1987). Effects of essential oils on erythrocytes and hepatocytes from rats and dipalmitoyl phosphatidylcholine-liposomes. Jpn J. Pharmacol. 44:77–84.
   PubMedGoogle Scholar
• Mansour, S.A., Messeha, S.S. and el-Gengaihi, S.E. (2000). Botanical biocides. 4. Mosquitocidal activity of certain Thymus capitatus constituents. J. Nat. Toxins 9:49–62.
   PubMedGoogle Scholar
• Marcos-Arias, C., Eraso, E., Madariaga, L. and Quindos, G. (2011). In vitro activities of natural products against oral Candida isolates from denture wearers. BMC Complement Altern Med. 11:119.
   PubMed Web of Science ®Google Scholar
• Mastelic, J., Jerkovic, I., Blazevic, I., Poljak-Blazi, M., Borovic, S., Ivancic-Bace, I., Smrecki, V., Zarkovic, N., Brcic-Kostic, K., Vikic-Topic, D. and Muller, N. (2008). Comparative study on the antioxidant and biological activities of carvacrol, thymol, and eugenol derivatives. J. Agric. Food Chem. 56:3989–3996.
   PubMed Web of Science ®Google Scholar
• Mathela, C.S., Singh, K.K. and Gupta, V.K. (2010). Synthesis and in vitro antibacterial activity of thymol and carvacrol derivatives. Acta Pol. Pharm. 67:375–380.
   PubMed Web of Science ®Google Scholar
• McOmie, W.A., Anderson, H.H. and Estess, F.M. (1949). Comparative toxicity of certain t-butyl substituted cresols and xylenols. J. Am. Pharm. Assoc. Am. Pharm. Assoc. 38:366–369.
   PubMedGoogle Scholar
• Melo, F.H., Moura, B.A., de Sousa, D.P., de Vasconcelos, S.M., Macedo, D.S., Fonteles, M.M., Viana, G.S. and de Sousa, F.C. (2011). Antidepressant-like effect of carvacrol (5-Isopropyl-2-methylphenol) in mice: involvement of dopaminergic system. Fundam. Clin. Pharmacol. 25:362–367.
   PubMed Web of Science ®Google Scholar
• Melo, F.H., Venancio, E.T., de Sousa, D.P., de Franca Fonteles, M.M., de Vasconcelos, S.M., Viana, G.S. and de Sousa, F.C. (2010). Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission. Fundam. Clin. Pharmacol. 24:437–443.
   PubMed Web of Science ®Google Scholar
• Miguel, M.G., Figueiredo, A.C., Costa, M.M., Martins, D., Duarte, J., Barroso, J.G. and Pedro, L.G. (2003). Effect of the volatile constituents isolated from Thymus albicans, Th. mastichina, Th. carnosus and Thymbra capitata in sunflower oil. Nahrung 47:397–402.
   PubMedGoogle Scholar
• Monzote, L., Stamberg, W., Staniek, K. and Gille, L. (2009). Toxic effects of carvacrol, caryophyllene oxide, and ascaridole from essential oil of Chenopodium ambrosioides on mitochondria. Toxicol. Appl. Pharmacol. 240:337–347.
   PubMed Web of Science ®Google Scholar
• Moraes, L.A., Piqueras, L. and Bishop-Bailey, D. (2006). Peroxisome proliferator-activated receptors and inflammation. Pharmacol. Ther. 110:371–385.
   PubMed Web of Science ®Google Scholar
• Moreira, P.I. and Oliveira, C.R. (2011). Mitochondria as potential targets in antidiabetic therapy. Handb. Exp. Pharmacol. 331–356.
   PubMedGoogle Scholar
• Nino, M., Calabro, G. and Santoianni, P. (2010). Topical delivery of active principles: the field of dermatological research. Dermatol. Online J. 16
   PubMedGoogle Scholar
• Nostro, A., Marino, A., Blanco, A.R., Cellini, L., Di Giulio, M., Pizzimenti, F., Sudano Roccaro, A. and Bisignano, G. (2009). In vitro activity of carvacrol against staphylococcal preformed biofilm by liquid and vapour contact. J. Med. Microbiol. 58:791–797.
   PubMed Web of Science ®Google Scholar
• Nostro, A., Sudano Roccaro, A., Bisignano, G., Marino, A., Cannatelli, M.A., Pizzimenti, F.C., Cioni, P.L., Procopio, F. and Blanco, A.R. (2007). Effects of oregano, carvacrol and thymol on Staphylococcus aureus and Staphylococcus epidermidis biofilms. J. Med. Microbiol. 56:519–523.
   PubMed Web of Science ®Google Scholar
• Nychas, G.J. E. (1995). Natural antimicrobials from plants. In: New Methods of Food Preservation, pp. 58–89. Gould, G.W. Ed., Aspen Publishers, Glasgow.
   Google Scholar
• Obaidat, R.M., Bader, A., Al-Rajab, W., Abu Sheikha, G. and Obaidat, A.A. (2011). Preparation of mucoadhesive oral patches containing tetracycline hydrochloride and carvacrol for treatment of local mouth bacterial infections and candidiasis. Sci. Pharm. 79:197–212.
   PubMedGoogle Scholar
• Olasupo, N.A., Fitzgerald, D.J., Narbad, A. and Gasson, M.J. (2004). Inhibition of Bacillus subtilis and Listeria innocua by nisin in combination with some naturally occurring organic compounds. J. Food Prot. 67:596–600.
   PubMed Web of Science ®Google Scholar
• Opdyke, D.L. (1979). Monographs on fragrance raw materials. Food Cosmet. Toxicol. 17:695–923.
   PubMedGoogle Scholar
• Park, B.S., Choi, W.S., Kim, J.H., Kim, K.H. and Lee, S.E. (2005). Monoterpenes from thyme (Thymus vulgaris) as potential mosquito repellents. J. Am. Mosq. Control. Assoc. 21:80–83.
   PubMed Web of Science ®Google Scholar
• Parnas, M., Peters, M., Dadon, D., Lev, S., Vertkin, I., Slutsky, I. and Minke, B. (2009). Carvacrol is a novel inhibitor of Drosophila TRPL and mammalian TRPM7 channels. Cell. Calcium. 45:300–309.
   PubMed Web of Science ®Google Scholar
• Pavela, R. (2011). Insecticidal properties of phenols on Culex quinquefasciatus Say and Musca domestica L. Parasitol. Res. 109:1547–1553.
   PubMed Web of Science ®Google Scholar
• Peixoto-Neves, D., Silva-Alves, K.S., Gomes, M.D., Lima, F.C., Lahlou, S., Magalhaes, P.J., Ceccatto, V.M., Coelho-de-Souza, A.N. and Leal-Cardoso, J.H. (2010). Vasorelaxant effects of the monoterpenic phenol isomers, carvacrol and thymol, on rat isolated aorta. Fundam. Clin. Pharmacol. 24:341–350.
   PubMed Web of Science ®Google Scholar
• Perez-Conesa, D., Cao, J., Chen, L., McLandsborough, L. and Weiss, J. (2011). Inactivation of Listeria monocytogenes and Escherichia coli O157:H7 biofilms by micelle-encapsulated eugenol and carvacrol. J. Food Prot. 74:55–62.
   PubMed Web of Science ®Google Scholar
• Perez-Conesa, D., McLandsborough, L. and Weiss, J. (2006). Inhibition and inactivation of Listeria monocytogenes and Escherichia coli O157:H7 colony biofilms by micellar-encapsulated eugenol and carvacrol. J. Food Prot. 69:2947–2954.
   PubMed Web of Science ®Google Scholar
• Phillips, A.K. and Appel, A.G. (2010). Fumigant toxicity of essential oils to the German cockroach (Dictyoptera: Blattellidae). J. Econ. Entomol. 103:781–790.
   PubMed Web of Science ®Google Scholar
• Phillips, M. (1924) The sulfonation of para-cymene. J. Am. Chem. Soc., 46:686–694.
   Google Scholar
• Pina-Vaz, C., Goncalves Rodrigues, A., Pinto, E., Costa-de-Oliveira, S., Tavares, C., Salgueiro, L., Cavaleiro, C., Goncalves, M.J. and Martinez-de-Oliveira, J. (2004) Antifungal activity of Thymus oils and their major compounds. J. Eur. Acad. Dermatol. Venereol. 18:73–78.
   PubMed Web of Science ®Google Scholar
• Radominska-Pandya, A., Ouzzine, M., Fournel-Gigleux, S. and Magdalou, J. (2005). Structure of UDP-glucuronosyltransferases in membranes. Methods Enzymol. 400:116–147.
   PubMed Web of Science ®Google Scholar
• Radonic, A. and Milos, M. (2003). Chemical composition and in vitro evaluation of antioxidant effect of free volatile compounds from Satureja montana L. Free Radic. Res. 37:673–679.
   PubMed Web of Science ®Google Scholar
• Rao, A., Zhang, Y., Muend, S. and Rao, R. (2010). Mechanism of antifungal activity of terpenoid phenols resembles calcium stress and inhibition of the TOR pathway. Antimicrob. Agents Chemother 54:5062–5069.
   PubMed Web of Science ®Google Scholar
• Rattanachaikunsopon, P. and Phumkhachorn, P. (2010). Assessment of factors influencing antimicrobial activity of carvacrol and cymene against Vibrio cholerae in food. J. Biosci. Bioeng. 110:614–619.
   PubMed Web of Science ®Google Scholar
• Ravishankar, S., Zhu, L., Law, B., Joens, L. and Friedman, M. (2008). Plant-derived compounds inactivate antibiotic-resistant Campylobacter jejuni strains. J. Food Prot. 71:1145–1149.
   PubMed Web of Science ®Google Scholar
• Ravishankar, S., Zhu, L., Reyna-Granados, J., Law, B., Joens, L. and Friedman, M. (2010). Carvacrol and cinnamaldehyde inactivate antibiotic-resistant Salmonella enterica in buffer and on celery and oysters. J. Food Prot. 73:234–240.
   PubMed Web of Science ®Google Scholar
• Ray, S.D. (2011). Potential aspects of chitosan as pharmaceutical excipient. Acta. Pol. Pharm. 68:619–622.
   PubMed Web of Science ®Google Scholar
• Ritter, J.J. and Ginsburg, D. (1950). Preparation of chlorination of alpha-pinene with tert-butyl hypochlorite. J. Am. Chem. Soc. 72:2381–2384.
   Web of Science ®Google Scholar
• Rivas, L., McDonnell, M.J., Burgess, C.M., O’Brien, M., Navarro-Villa, A., Fanning, S. and Duffy, G. (2010). Inhibition of verocytotoxigenic Escherichia coli in model broth and rumen systems by carvacrol and thymol. Int. J. Food Microbiol. 139:70–78.
   PubMed Web of Science ®Google Scholar
• Roller, S. and Seedhar, P. (2002). Carvacrol and cinnamic acid inhibit microbial growth in fresh-cut melon and kiwifruit at 4 degrees and 8 degrees C. Lett. Appl. Microbiol. 35:390–394.
   PubMed Web of Science ®Google Scholar
• Sarkozi, S., Almassy, J., Lukacs, B., Dobrosi, N., Nagy, G. and Jona, I. (2007). Effect of natural phenol derivatives on skeletal type sarcoplasmic reticulum Ca2 +-ATPase and ryanodine receptor. J. Muscle. Res. Cell. Motil. 28:167–174.
   PubMed Web of Science ®Google Scholar
• Sasaki, K., Wada, K., Tanaka, Y., Yoshimura, T., Matuoka, K. and Anno, T. (2005). Thyme (Thymus vulgaris L.) leaves and its constituents increase the activities of xenobiotic-metabolizing enzymes in mouse liver. J. Med. Food 8:184–189.
   PubMedGoogle Scholar
• Schroder, J. and Vollmer, H. (1932). The excretion of thymol, carvacrol, eugenol and guaiacol and the distribution of these substances in the organism. Arch. Exp. Path. Pharmakol. 168:331–353.
   Google Scholar
• Shoji, Y. and Nakashima, H. (2004). Nutraceutics and delivery systems. J. Drug. Target 12:385–391.
   PubMed Web of Science ®Google Scholar
• Slamenova, D., Horvathova, E., Chalupa, I., Wsolova, L. and Navarova, J. (2011). Ex vivo assessment of protective effects of carvacrol against DNA lesions induced in primary rat cells by visible light excited methylene blue (VL+MB). Neoplasma 58:14–19.
   PubMed Web of Science ®Google Scholar
• Slamenova, D., Horvathova, E., Marsalkova, L. and Wsolova, L. (2008). Carvacrol given to rats in drinking water reduces the level of DNA lesions induced in freshly isolated hepatocytes and testicular cells by H(2)O(2). Neoplasma 55:394–399.
   PubMed Web of Science ®Google Scholar
• Slamenova, D., Horvathova, E., Sramkova, M. and Marsalkova, L. (2007). DNA-protective effects of two components of essential plant oils carvacrol and thymol on mammalian cells cultured in vitro. Neoplasma 54:108–112.
   PubMed Web of Science ®Google Scholar
• Smith, P.A., Sorich, M.J., McKinnon, R.A. and Miners, J.O. (2003). Pharmacophore and quantitative structure-activity relationship modeling: complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity. J. Med. Chem. 46:1617–1626.
   PubMed Web of Science ®Google Scholar
• Sokmen, M., Serkedjieva, J., Daferera, D., Gulluce, M., Polissiou, M., Tepe, B., Akpulat, H.A., Sahin, F. and Sokmen, A. (2004). In vitro antioxidant, antimicrobial, and antiviral activities of the essential oil and various extracts from herbal parts and callus cultures of Origanum acutidens. J. Agric. Food Chem. 52:3309–3312.
   PubMed Web of Science ®Google Scholar
• Sompolinsky, D. and Samra, Z. (1981). Plasmid-determined resistance to tetracycline. Microbios 30:109–130.
   PubMedGoogle Scholar
• Songkro, S., Rades, T. and Becket, G. (2009). Effects of some terpenes on the in vitro permeation of LHRH through newborn pig skin. Pharmazie 64:110–115.
   PubMed Web of Science ®Google Scholar
• Stammati, A., Bonsi, P., Zucco, F., Moezelaar, R., Alakomi, H.L. and von Wright, A. (1999). Toxicity of selected plant volatiles in microbial and mammalian short-term assays. Food. Chem. Toxicol. 37:813–823.
   PubMed Web of Science ®Google Scholar
• Stella, V.J. and He, Q. (2008). Cyclodextrins. Toxicol. Pathol. 36:30–42.
   PubMed Web of Science ®Google Scholar
• Suntres, Z.E. (2011). Liposomal antioxidants for protection against oxidant-induced damage. J. Toxicol. 2011:152474.
   PubMedGoogle Scholar
• Tang, X., Chen, S. and Wang, L. (2011). Purification and identification of carvacrol from the root of Stellera chamaejasme and research on its insecticidal activity. Nat. Prod. Res. 25:320–325.
   PubMed Web of Science ®Google Scholar
• Teissedre, P.L. and Waterhouse, A.L. (2000). Inhibition of oxidation of human low-density lipoproteins by phenolic substances in different essential oils varieties. J. Agric. Food Chem. 48:3801–3805.
   PubMed Web of Science ®Google Scholar
• Tepe, B., Daferera, D., Sokmen, M., Polissiou, M. and Sokmen, A. (2004). In vitro antimicrobial and antioxidant activities of the essential oils and various extracts of Thymus eigii M. Zohary et P. H. Davis. J. Agric. Food Chem. 52:1132–1137.
   PubMed Web of Science ®Google Scholar
• Ueda, T., Yamada, T., Ugawa, S., Ishida, Y. and Shimada, S. (2009). TRPV3, a thermosensitive channel is expressed in mouse distal colon epithelium. Biochem. Biophys. Res. Commun. 383:130–134.
   PubMed Web of Science ®Google Scholar
• Ündeger, Ü., Basaran, A., Degen, G.H. and Basaran, N. (2009). Antioxidant activities of major thyme ingredients and lack of (oxidative) DNA damage in V79 Chinese hamster lung fibroblast cells at low levels of carvacrol and thymol. Food Chem. Toxicol. 47:2037–2043.
   PubMed Web of Science ®Google Scholar
• Ultee, A., Bennik, M.H. and Moezelaar, R. (2002). The phenolic hydroxyl group of carvacrol is essential for action against the food-borne pathogen Bacillus cereus. Appl. Environ. Microbiol. 68:1561–1568.
   PubMed Web of Science ®Google Scholar
• Ultee, A., Kets, E.P., Alberda, M., Hoekstra, F.A. and Smid, E.J. (2000a). Adaptation of the food-borne pathogen Bacillus cereus to carvacrol. Arch. Microbiol. 174:233–238.
   PubMed Web of Science ®Google Scholar
• Ultee, A., Kets, E.P. and Smid, E.J. (1999). Mechanisms of action of carvacrol on the food-borne pathogen Bacillus cereus. Appl. Environ. Microbiol. 65:4606–4610.
   PubMed Web of Science ®Google Scholar
• Ultee, A., Slump, R.A., Steging, G. and Smid, E.J. (2000b). Antimicrobial activity of carvacrol toward Bacillus cereus on rice. J. Food Prot. 63:620–624.
   PubMed Web of Science ®Google Scholar
• Uyanoglu, M., Canbek, M., Aral, E. and Husnu Can Baser, K. (2008). Effects of carvacrol upon the liver of rats undergoing partial hepatectomy. Phytomedicine 15:226–229.
   PubMed Web of Science ®Google Scholar
• Vaddi, H.K., Ho, P.C. and Chan, S.Y. (2002). Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry. J. Pharm. Sci. 91:1639–1651.
   PubMed Web of Science ®Google Scholar
• Van Den Broucke, C.O. and Lemli, J.A. (1980). Antispasmodic activity of Origanum compactum. Planta Med. 38:317–331.
   PubMed Web of Science ®Google Scholar
• Van Den Broucke, C.O. and Lemli, J.A. (1982). Antispasmodic Activity of Origanum compactum. Planta. Med. 45:188–190.
   PubMed Web of Science ®Google Scholar
• Vardar-Unlu, G., Yagmuroglu, A. and Unlu, M. (2010). Evaluation of in vitro activity of carvacrol against Candida albicans strains. Nat. Prod. Res. 24:1189–1193.
   PubMed Web of Science ®Google Scholar
• Vokou, D., Kokkini, S. and Bessiere, J.M. (1993). Geographical variation of Greek oregano (Origanum vulgare ssp. hirtum) essential oils. Biochem. Syst. Ecol. 21:287–295.
   Web of Science ®Google Scholar
• Wang, Q., Gong, J., Huang, X., Yu, H. and Xue, F. (2009) In vitro evaluation of the activity of microencapsulated carvacrol against Escherichia coli with K88 pili. J. Appl. Microbiol. 107:1781–1788.
   PubMed Web of Science ®Google Scholar
• Wienkers, L.C. and Heath, T.G. (2005). Predicting in vivo drug interactions from in vitro drug discovery data. Nat. Rev. Drug. Discov. 4:825–833.
   PubMed Web of Science ®Google Scholar
• Wong, S.Y., Grant, I.R., Friedman, M., Elliott, C.T. and Situ, C. (2008). Antibacterial activities of naturally occurring compounds against Mycobacterium avium subsp. paratuberculosis. Appl. Environ. Microbiol. 74:5986–5990.
   PubMed Web of Science ®Google Scholar
• Xu, H., Delling, M., Jun, J.C. and Clapham, D.E. (2006). Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat. Neurosci. 9:628–635.
   PubMed Web of Science ®Google Scholar
• Yadav, G.D. and Kamble, S.B. (2009). Synthesis of carvacrol by Friedel–Crafts alkylation of o-cresol with isopropanol using superacidic catalyst UDCaT-5. J. Chem. Technol. Biotechnol. 84:1499–1508.
   Web of Science ®Google Scholar
• Yamada, T., Ueda, T., Ugawa, S., Ishida, Y., Imayasu, M., Koyama, S. and Shimada, S. (2010). Functional expression of transient receptor potential vanilloid 3 (TRPV3) in corneal epithelial cells: Involvement in thermosensation and wound healing. Exp. Eye. Res. 90:121–129.
   PubMed Web of Science ®Google Scholar
• Yessoufou, A. and Wahli, W. (2010). Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels. Swiss. Med. Wkly. 140:w13071.
   PubMed Web of Science ®Google Scholar
• Yin, Q.H., Yan, F.X., Zu, X.Y., Wu, Y.H., Wu, X.P., Liao, M.C., Deng, S.W. , Yin, L.L. and Zhuang, Y.Z. (2012). Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2. Cytotechnology 64:43–51.
   PubMed Web of Science ®Google Scholar
• Zeytinoglu, M., Aydin, S., Ozturk, Y., Husnu, K. and Baser, C (1998). Inhibitory effects of carvacrol on DMBA induced pulmonary tumorigenesis in rats. Acta. Pharmaceutica Turcica 40:93–98.
   Google Scholar