Hepatoprotective Effect of Caffeic Acid Phenethyl Ester (CAPE) on Carbon Tetrachloride (CCI4) Induced Acute Hepatotoxicity in Rats

Süleyman Özen 1 * , Hayal Oral 2, Hanefi Özbek 3
More Detail
1 Yüzüncü Yıl University Medical School, Department of Pathology, Van, Turkey
2 Adana Government Hospital, Department of Pathology, Adana, Turkey
3 The Ministry of Health, Drug Agency, Ankara, Turkey
* Corresponding Author
EUR J BASIC MED SCI, Volume 1, Issue 1, pp. 7-12. https://doi.org/10.21601/ejbms/9161
Download Full Text (PDF)


In this study, hepatoprotective activity of CAPE, which has antiinflammatory, anticancer, antiviral, and immunomodulatory effects, was investigated in the CCI4 induced liver injury model in rats. Twenty-one Sprague Dawley rats were divided into the three groups: Control (n=7), CCI4 (n=7), CCI4 + CAPE (n=7). The serum levels of AST, ALT, LDH, and bilirubin were measured on the first and last day (10 th day) in all experimental animals. Histopathological examinations were carried out in the rats sacrificed on the tenth day. For histopathological evaluation, livers of all rats were removed and processed for light microscopy. The levels of unconjugated bilirubin, AST, ALT, ALP in CCI4 group were markedly higher than those in the control group (p<0.01, p<0.01, p<0.001 and p<0.05 respectively). The values of these parameters in CAPE+CCI4 group were lower than those in CCI4 (p<0.01, p<0.05, p<0.05, p<0.001 respectively). Histopathological findings also corfirmed that CCI4 induced hepadic damage and support the wiev that CAPE has a hepatoprotective activity. The results of this study indicate that CAPE has a hepatoprotective action in acute liver injury.


Özen S, Oral H, Özbek H. Hepatoprotective Effect of Caffeic Acid Phenethyl Ester (CAPE) on Carbon Tetrachloride (CCI4) Induced Acute Hepatotoxicity in Rats. Eur J Basic Med Sci. 2011;1(1):7-12. https://doi.org/10.21601/ejbms/9161


  • Stacey N, Priestly BG. Dose-dependent toxicity of CCl4 in isolated rat hepatocytes and the effects of hepatoprotective treatments. Toxicol Appl Pharmacol 1978;45:29–39.
  • Kodavanti PR, Joshi UM, Young RA, Meydrech EF, Mehendale HM. Protection of hepatotoxic and lethal effects of CCl4 by partial hepatectomy. Toxicol Pathol 1989;17:494–505.
  • Brattin WJ, Glende Jr EA, Recknagel RO. Pathological mechanisms in carbon tetrachloride hepatotoxicity. J Free Radic Biol Med 1985;1:27–38.
  • Rechnagel RO, Glende Jr EA. Carbon tetrachloride hepatotoxicity: an example of lethal cleavage. CRC Crit Rev Toxicol 1973;2:263–97.
  • Rikans LE, Hornbrook KR, Cai Y. Carbon tetrachloride hepatotoxicity as a function of age in female Fischer 344 rats. Mech Ageing Dev 1994;76:89–99.
  • Teocharis SE, Margeli AP, Skaltsas SD, Spiliopoulou CA, Koutselinis AS. Induction of metallothionein in the liver of carbon tetrachloride intoxicated rats: an immunohistochemical study. Toxicology 2001;161:129–38.
  • Naziroglu M, Cay M, Ustundag B, Aksakal M, Yekeler H. Protective effects of vitamin E on carbon tetrachloride- induced liver damage in rats. Cell Biochem Funct 1999;17:253–9.
  • Natsume M, Tsuji H, Harada A, Akiyama M, Yano T, Ishikura H, Nakanishi I, Matsushima K, Kaneko S, Mukaida N. Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice. J Leukoc Biol 1999;66: 601–8.
  • Wang GS, Eriksson LC, Xia L, Olsson J, Stal P. Dietary iron overload inhibits carbon tetrachloride-induced promotion in chemical hepatocarcinogenesis: effects on cell proliferation, apoptosis and antioxidation. J Hepathol 1999;30:689–98.
  • Zalatnai A, Sarosi I, Rot A, Lapis K. Inhibitory and promoting effects of carbon tetrachloride-induced liver cirrhosis on the diethylnitrosamine hepatocarcinogenesis in rats. Cancer Lett 1991;57:67–73.
  • Grunberger D, Banerjee R, Eisinger K, et al. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 1988;44:230–32.
  • Chen YJ, Shiao MS, Wang SY. The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells. Anticancer Drugs 2001;12:143–49.
  • Park EH, Kahng JH. Suppressive effects of propolis in rat adjuvant arthritis. Arch Pharm Res 1999;22:554–8.
  • Nagaoka T, Banskota AH, Tezuka Y, Midorikawa K, Matsushige K, Kadota S. Caffeic acid phenethyl ester (CAPE) analogues: potent nitric oxide inhibitors from the Netherlands propolis. Biol Pharm Bull 2003;26:487–91.
  • Ilhan A, Iraz M, Gurel A, Armutcu F, Kyol O. Caffeic acid phenethyl ester exerts a neuroprotective effect on CNS against pentylenetetrazol-induced seizures in mice. Neurochem Res 2004;29:2287–92.
  • Hishikawa K, Nakaki T, Fujita T. Oral flavonoid supplementation attenuates atherosclerosis development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2005;25:442–6.
  • Rao C, Desai D, Kaul B, Amin S, Reddy BS. Effect of caffeic acid esters on carcinogen-induced mutagenicity and human colon adenocarcinoma cell growth. Chem Biol Interact 1992;84:277–290.
  • Kus I, Colakoglu N, Pekmez H, Seckin D, Ogeturk M, Sarsilmaz M. Protective effects of caffeic acid phenethyl ester (CAPE) on carbon tetrachlorideinduced hepatotoxicity in rats. Acta. Histochem 2004;106:289–97.
  • Ogeturk M, Kus I, Colakoglu N, Zararsiz I, Ilhan N, Sarsilmaz M. Caffeic acid phenethyl ester protects kidneys against carbon tetrachloride toxicity in rats. J. Ethnopharmacol 2005;97:273–80.
  • Ozen S, Akyol O, Iraz M, et al. Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin-induced nephrotoxicity in rats. J. Appl. Toxicol. 2004;24: 27–35.
  • Lee KJ, Choi JH, Khanal T, Hwang YP, Chung YC, Jeong HG. Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice. Toxicology 2008;248:18–24.
  • Iraz M, Ozerol E, Gulec M, et al. Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat. Cell Biochem Funct 2006;24:357–61.
  • Sud’ina GF, Mirzoeva OK, Pushkareva MA, Korshunova GA, Sumbatyan NV, Varfolomeev SD. Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett 1993; 329: 21–24.
  • Hepsen IF, Bayramlar H, Gultek A, Ozen S, Tilgen F, Evereklioglu C. Caffeic acid phenethyl ester to inhibit posterior capsule opacification in rabbits. J Cataract Refract Surg 1997;23: 1572– 6.
  • Hepsen IF, Er H, Cekic O. Topically applied water extract of propolis to suppress corneal neovascularization in rabbits. Ophthal Res 1999;31:426–31.
  • Ilhan A, Koltuksuz U, Ozen S, Uz E, Ciralik H, Akyol O. The effects of caffeic acid phenethyl ester (CAPE) on spinal cord ischemia/reperfusion injury in rabbits. Eur J Cardiothorac Surg 1999;16:458–63.
  • Koltuksuz U, Ozen S, Uz E, Aydinc M, Karaman A, Gultek A, et al. Caffeic acid phenethyl ester (CAPE) prevents intestinal reperfusion injury in rats. J Pediatr Surg 1999;34:1458– 62.
  • Fadillioglu E, Oztas E, Erdogan H, et al. Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats. J Appl Toxicol 2004; 24: 47–52.
  • National Institutes of Health, USA. Guide for the Care and Use of Laboratory Animals. DHEW Publication No. 85–23, NIH, 1985.
  • Brautbar N, Williams II J. Industrial solvents and liver toxicity: risk assessment, risk factors and mechanisms. Int J Hyg Environ Health 2002;205:479–91.
  • Brent JA, Rumack BH. Role of free radicals in toxic hepatic injury. II. Are free radicals the cause of toxin-induced liver injury? J Toxicol Clin Toxicol 1993;31:173–96.
  • Manibusan MK, Odin M, Eastmond DA. Postulated carbon tetrachloride mode of action: a review. J Environ Sci Health 2007;25:185–209.
  • Recknagel RO, Glende Jr, EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther 1989;43:139–54.
  • Mansour MA. Protective effects of thymoquinone and desferrioxamine against hepatotoxicity of carbon tetrachloride in mice. Life Sci 2000;66:2583–91.
  • Al-Shabanah OA, Alam K, Nagi MN, Al-Rikabi AC, Al-Bekairi AM. Protective effect of aminoguanidine, a nitric oxide synthase inhibitor, against carbon tetrachloride induced hepatotoxicity in mice. Life Sci 2000;66:265–70.
  • Zalatnai A, Sarosi I, Rot A, Lapis K. Inhibitory and promoting effects of carbon tetrachloride-induced liver cirrhosis on the diethylnitrosamine hepatocarcinogenesis in rats. Cancer Lett 1991;57:67–73.
  • Burr AW, Carpenter MR, Hines JE, Gullick WJ, Burt AD. Intrahepatic distribution of transforming growth factoralpha (TGF-a) during liver regeneration following carbon tetrachloride-induced necrosis. J Pathol1993;170:95–100.
  • Shi J, Aisaka K, Ikawa Y, Wake K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol 1998;153:515–25.
  • Cabre M, Ferre N, Folch J, Paternain JL, Hernandez M, del Castillo D, Joven J, Camps J. Inhibition of hepatic cell nuclear DNA fragmentation by zinc in carbon tetrachloride- treated rats. J Hepathol 1999;31: 228–34.
  • Ozyurt H, Irmak MK, Akyol O, Sogut S. Caffeic acid phenethyl ester changes the indices of oxidative stress in serum of rats with renal ischemia – reperfusion injury. Cell Biochem Funct 2001;19:259–63.
  • Sahin S, Sogut S, Ozyurt H, Uz E, Ilhan A, Akyol O. Tissue xanthine oxidase activity and nitric oxide levels after spinal cord ischemia/reperfusion injury in rabbits: comparison of caffeic acid phenethyl ester (CAPE) and methylprednisolone. Neurosci Res Commun 2002;31:111– 21.
  • Irmak MK, Koltuksuz U, Kutlu NO, Yagmurca M, Ozyurt H, Akyol O. The effect of caffeic acid phenethyl ester on ischemia– reperfusion injury in comparison with a-tocopherol in rat kidneys. Urol Res 2001;29:190–3.
  • Altug ME, Serarslan Y, Bal R, et al. Caffeic acid phenethyl ester protects rabbit brains against permanent focal ischemia by antioxidant action: a biochemical and planimetric study. Brain Res 2008;1201:135–142.
  • Scapagnini G, Foresti R, Calabrese V, et al. Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers. Mol Pharmacol 2002;61:1264.
  • Naugler WE, Sakurai T, Kim S. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317:121–4.
  • Orban Z, Mitsiades N, Burke Jr TR, Tsokos M, Chrousos GP. Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation 2000;7:99–105.
  • Choi K, Han YH, Choi C. N-Acetyl cysteine and caffeic acid phenethyl ester sensitize astrocytoma cells to Fas-mediated cell death in a redox-dependent manner. Cancer Lett 2007;257:79–86.