Protective effect of N-acetylcysteine,caffeic acid and vitamin E on doxorubicin hepatotoxicity

Abstract

The aim of this study was to compare the possible protective effects of N-acetylcysteine (NAC), caffeic acid (CAPE) and vitamin E (Vit-E) on doxorubicin-induced hepatotoxicity. Thirty-two male Wistar albino rats, weighing between 250 and 350 g were supplied and randomly divided into five groups. Animals in study groups were pretreated with a single dose of doxorubicin (Dox), which was administered intraperitoneally (i.p.). Control group (Group I) was treated with intraperitoneal saline injection. Group II did not received any antioxidant agent after the injection. Group III and Group IV were given CAPE and intraperitoneal vitamin E injection for eight days, respectively. Group V received NAC for eight days. The study was finished after 10 days. Tissue samples were collected from all animals and histopathological examination was performed. There was statistically significant difference between the experiment groups and controls by means of mononuclear cell infiltration and diameters of hepatic sinusoid, terminal hepatic venule (central vein) and portal area (portal canal). Changes related with hepatocellular damage were more prominent, whereas there was no significant difference between Dox and NAC given groups histopathologically. It was observed that structural changes were regressed after CAPE administration. However, this recovery was more prominent in vitamin E given group. These findings suggest that Dox induced liver damage could be efficiently reversed by vitamin E administration. It has been found that CAPE, but not NAC has protective effects on Dox-induced hepatocellular damage. Human & Experimental Toxicology (2007) 26 , 519—525

Keywords

caffeic acid doxorubicin hepatotoxicity N-acetylcysteine vitamin E

References

Yilmaz S. , Atessahin A. , Sahna E. , Karahan I. , Ozer S. Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity . Toxicology 2006; 218: 164—71.

Mataix J. , Manas M. , Quiles J. , Battino M. , Cassinello M. , Lopez-Frias M. , Huertas JR Coenzyme Q content depends upon oxidative stress and dietary fat unsaturation . Mol Aspects Med 1997; 18: 129—35.

Quiles JL , Huertas JR , Battino M. , Mataix J. , Ramirez-Tortosa MC Antioxidant nutrients and adriamycin toxicity. Toxicology 2002; 180: 79—95.

Singal PK , Li T. , Kumar D. , Danelisen I. , Iliskovic N. Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 2000; 207: 77—86.

De Beer EL , Bottone AE , Voest EE Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. Eur J Pharmacol 2001; 415: 1—11.

Kang J. , Lee Y. , No K. , Jung E. , Sung J. , Kim Y. , Nam S. Ginseng intestinal metabolite-I (GIM-I) reduces doxorubicin toxicity in the mouse testis. Reprod Toxicol 2002; 16: 291—98.

Atessahin A. , Karahan I. , Turk G. , Gur S. , Yilmaz S. , Ceribasi AO Protective role of lycopene on cisplatin-induced changes in sperm characteristics, testicular damage and oxidative stress in rats. Reprod Toxicol 2005a; in press.

Atessahin A. , Yilmaz S. , Karahan I. , Ceribasi AO , Karaoglu A. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 2005b; 212: 16—23.

King PD , Perry MC The hepatotoxicity of chemotherapy. Oncologist 2001; 6: 162—76.

10.

Liu Y. , Thurman RG Potentiation of adriamycin toxicity by ethanol in perfused rat liver. J Pharmacol Exp Ther 1992; 263: 651—56.

11.

Pedrycz A. , Wieczorski M. , Czerny K. The influence of a single dose of adriamycin on the pregnant rat female liver-histological and histochemical evaluation. Ann Univ Mariae Curie Sklodowska [Med] 2004; 59: 319—23.

12.

Zeidan Q. , Strauss M. , Porras N. , Anselmi G. Differential long-term subcellular responses in heart and liver to adriamycin stress. Exogenous L-carnitine cardiac and hepatic protection. J Submicrosc Cytol Pathol 2002; 34: 315—21.

13.

Kimura T. , Fujita I. , Itoh N. , Muto N. , Nakanishi T. , Takahashi K. , Azuma J. , Tanaka K. Metallothionein acts as a cytoprotectant against doxorubicin toxicity. J Pharmacol Exp Ther 2002; 292: 299—302.

14.

Al-Bekairi AM , Abdel-Moneim MO , Hafeez MA , Al-Gharably NM , Al-Shabanah OA , Al-Harbi MM Effect of desferrioxamine on the hepatotoxicity of adriamycin in normal mice. Drug Development Research 1993; 29: 56—62.

15.

Deepa PR , Varalakshmi P. Protective effect of low molecular weight heparin on oxidative injury and cellular abnormalities in adriamycin-induced cardiac and hepatic toxicity . Chem Biol Interact 2003; 146: 201—10.

16.

Kalender Y. , Yel M. , Kalender S. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicology 2005; 209: 39—45.

17.

Powell SR , McCay PB Inhibition of doxorubicin-induced membrane damage by thiol compounds: toxicologic implications of a glutathione-dependent microsomal factor. Free Radic Biol Med 1995; 18: 159—68.

18.

Natarajan K. , Singh S. , Burke TR Jr , Grunbergert D. , Aggarwal BB Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-KB. Proc Natl Acad Sci USA 1996; 93: 9090—95.

19.

Iraz M. , Ozerol E. , Gulec M. , Tasdemir S. , Idiz N. , Fadillioglu E. , Naziroglu M. , Akyol O. Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat. Cell Biochem Funct 2006 [Epub ahead of print].

20.

White WJ The use of laboratory animals in toxicologic research. In, AW Hayes ed. Principles and method of toxicology (4th edition). Taylor & Francis 2001: 774—818.

21.

Gokcimen A. , Aydin G. , Karaöz E. , Malas MA Effect of diclofenac sodium administration during pregnancy in the postnatal period. Fetal Diagn Ther 2001; 16: 417—22.

22.

Tsuhamato H. , Towner J. Ethanol-induced liver fibrosis in rats fed high-fat diet. Hepatolog 1986; 6: 814—22.

23.

Pedrycz A. , Wieczorski M. , Czerny K. Increased apoptosis in the adult rat liver after a single dose of adriamycin administration. Ann Univ Mariae Curie Sklodowska [Med] 2004; 59: 313—18.

24.

Doroshow JH Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase. Cancer Research 1983; 43: 4543—51.

25.

Ganey PE , Kauffman FC , Thurman RG Oxygen-dependent hepatotoxicity due to doxorubicin: role of reducing equivalent supply in perfused rat liver. Mol Pharmacol 1988; 34: 695—701.

26.

Song YS , Park EH , Hur GM , Ryu YS , Lee YS , Lee JY , Kim YM , Jin C. Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. Cancer Letters 2002; 175: 53—61.

27.

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.

28.

Irmak MK , Koltuksuz U. , Kutlu NO , Yagmurca M. , Ozyurt H. , Karaman A. , Akyol O. The effect of caffeic acid phenethyl ester on ischemia-reperfusion injury in comparison with alpha-tocopherol in rat kidneys. Urological Research 2001; 29: 190—93.

29.

Irmak MK , Fadillioglu E. , Sogut S. , Erdogan H. , Gulec M. , Ozer M. , Yagmurca M. , Gozukara ME Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain. Cell Biochem Funct 2003 ; 21: 283—89.

30.

Kalender S. , Kalender Y. , Ogutcu A. , Uzunhisarcikli M. , Durak D. , Acikgoz F. Endosulfan-induced cardiotoxicity and free radical metabolism in rats: the protective effect of vitamin E. Toxicology 2004; 202: 227—35.