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Histologic Examination of the Protective Effect of Vitamin E and C in Cisplatin-Induced Hepatotoxicity

Yıl 2005, Cilt: 2005 Sayı: 3, 124 - 131, 01.03.2005

Öz

Objectives: We investigated the morphologic changes showing hepatocellular damage caused by the chronic use of cisplatin, an antineoplastic agent, and the protective effect of vitamins E and C. Study Design: Twenty-four Wistar albino male rats were randomly assigned to four groups, equal in number, to receive intravenous 5 mg/kg of cisplatin once a month for three months except for the control rats (group 1). The rats in group 3 and 4 also received daily intramuscular injections of 5 mg/kg of vitamin E and 8 mg/kg of vitamin C, respectively. At the end of three months, the livers were removed for light and electron microscopic examinations. Results: Control rats showed a normal liver tissue structure. Group 2 rats exhibited disorganization of the Remak's fibers, thickening of the basement membrane together with dilatation of the sinusoids near the centrolobular vein, and lymphocyte infiltration in the portal areas. In vitamin E-treated rats, there was a significant decrease in morphological damage, with disappearance of lymphocyte infiltration in the portal areas. Vitamin C-treated rats manifested the least morphological damage, with a rare infiltration to portal areas and decreased number of infiltration cells. Conclusion: Our findings suggest that the use of antioxidants of different properties may help reduce cisplatin hepatotoxicity, thus contributing to clinical applications. Turkish Başlık: E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi Anahtar Kelimeler: Antineoplastik ajan; cisplatin/toksisite/yan etki; karaciğer/ilaç etkisi; sıçan; vitamin C/terapötik kullanım; vitamin E/terapötik kullanım Amaç: Bu çalışmada, bir antineoplastik ajan olan cisplatinin kronik uygulandığında yol açtığı karaciğer hasarı ve bu hasara karşı E ve C vitaminlerinin ne ölçüde koruma sağlayacağı histolojik olarak incelendi. Çalışma Planı: Çalışmada, 24 adet Wistar albino cinsi erkek sıçan altışarlı dört gruba ayrıldı. Kontrol grubu dışındaki (grup 1) deneklere üç ay boyunca, ayda bir kez 5 mg/kg cisplatin intravenöz yolla verildi. Grup 3 ve 4'teki deneklere ise ayrıca, her gün intramusküler yolla sırasıyla 5 mg/kg E vitamini ve 8 mg/kg C vitamini verildi. Deney süresinin sonunda, tüm deneklerin karaciğer materyalleri alınarak ışık ve elektron mikroskobisi ile incelendi. Bulgular: Kontrol grubu deneklerde normal yapıda karaciğer dokusu gözlendi. İkinci grupta Remak kordonları nda düzensizleşme, V. centrolobularis'e yakın sinüzoidlerde genişleme ile birlikte bazal membranlarda kalınlaşma, portal sahalarda ise lenfosit infiltrasyonu görüldü. Üçüncü grupta morfolojik hasarı n büyük oranda azaldığı, çoğu portal sahada lenfosit infiltrasyonunun ortadan kalktığı; dördüncü grupta ise düzelmenin daha da belirginleşerek portal saha infiltrasyon bölge sayısının hem seyreldiği hem de infiltrasyon hücre sayısının çok azaldığı görüldü. Sonuç: Farklı özelliklere sahip antioksidanların cisplatinin hepatotoksisitesinin azalmasına yardımcı olarak klinik uygulamaya katkıda bulunacağı sonucuna varıldı.

Kaynakça

  • Naziroglu M, Karaoglu A, Aksoy AO. Selenium and high dose vitamin E administration protects cis- platin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 2004;195:221-30.
  • Antunes LM, Darin JD, Bianchi Nde L. Effects of the antioxidants curcumin or selenium on cisplatin- induced nephrotoxicity and lipid peroxidation in rats. Pharmacol Res 2001;43:145-50.
  • Cersosimo RJ. Hepatotoxicity associated with cis- platin chemotherapy. Ann Pharmacother 1993;27:438-41.
  • Liu J, Liu Y, Habeebu SS, Klaassen CD. Metallothionein (MT)-null mice are sensitive to cis- platin-induced hepatotoxicity. Toxicol Appl Pharmacol 1998;149:24-31.
  • Imamura Y, Hirata M, Takada H, Otagiri M. Acetohexamide reductase activities in liver micro- somes and cytosol of cisplatin-treated male rats: cis- platin indirectly modulates the microsomal enzyme activity. Res Commun Mol Pathol Pharmacol 1996;94:203-10.
  • Stewart DJ, Mikhael NZ, Nanji AA, Nair RC, Kacew S, Howard K, et al. Renal and hepatic concentrations of platinum: relationship to cisplatin time, dose, and nephrotoxicity. J Clin Oncol 1985;3:1251-6.
  • Zicca A, Cafaggi S, Mariggio MA, Vannozzi MO, Ottone M, Bocchini V, et al. Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats. Eur J Pharmacol 2002;442:265-72.
  • Welters MJ, Fichtinger-Schepman AM, Baan RA, Jacobs-Bergmans AJ, Kegel A, van der Vijgh WJ, et al. Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum con- tent, DNA adduct levels and drug sensitivity in vitro and in vivo. Br J Cancer 1999;79:82-8.
  • Chu G. Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. J Biol Chem 1994;269:787-90.
  • Capel ID, Leach D, Dorrell HM. Vitamin E retards the lipoperoxidation resulting from anticancer drug administration. Anticancer Res 1983;3:59-62.
  • el Daly ES. Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cis- platin-induced toxicity in rats. J Pharm Belg 1998;53:87-93; discussion 93-5.
  • Sadzuka Y, Shoji T, Takino Y. Effect of cisplatin on the activities of enzymes which protect against lipid peroxidation. Biochem Pharmacol 1992;43:1872-5.
  • Ramanathan K, Shila S, Kumaran S, Panneerselvam C. Ascorbic acid and alpha-tocopherol as potent modulators on arsenic induced toxicity in mitochon- dria. J Nutr Biochem 2003;14:416-20.
  • Senyelli B. İntraperitoneal mitomisin C ile geliştiri- len deneysel kolitte antioksidanların etkisi. [Uzman- lık Tezi]. Edirne: Trakya Üniversitesi Tıp Fakültesi İç Hastalıkları Anabilim Dalı; 1999.
  • Murray RK, Granner DK, Mayes PA, Rodwell VW, editors. Yağda çözünen vitaminlerin yapı ve fonksiyonu. In: Harper’in biyokimyası (Harper's biochemistry. 22nd ed. Norwalk, CT: Appleton and Lange; 1990.) Çeviri editörü: Menteş G, Ersöz B. İstanbul: Barış Kitabevi; 1993. s. 711-2.
  • Padh H. Vitamin C: newer insights into its biochem- ical functions. Nutr Rev 1991;49:65-70.
  • Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 1999;13:1007-24.
  • Demir R, editör. Histolojik boyama teknikleri başvuru kitabı. Ankara: Palme yayıncılık; 2001.
  • Gabe M. Les principes généraux de la technique his- tologique. Paris: Masson et Cie; 1968. p. 10-30.
  • Hayat MA. Principles and techniques of electron microscopy: biological applications. 1st ed. USA: Van Nostrand Reinhold Company; 1970.
  • Wang K, Shindoh H, Inoue T, Horii I. Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines. J Toxicol Sci 2002;27:229-37.
  • Poklis A. Toxic responses of the liver. In: Klaassen CD, editor. Casarett & doull’s toxicology. Fifth ed: New York: The McGraw Hill Co; 1996. p. 403-15.
  • Briz O, Serrano MA, Rebollo N, Hagenbuch B, Meier PJ, Koepsell H, et al. Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis- diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells. Mol Pharmacol 2002;61:853-60.
  • Villanueva GR, Mendoza ME, el-Mir MY, Monte MJ, Herrera MC, Marin JJ. Effect of bile acids on hepato- biliary transport of cisplatin by perfused rat liver. Pharmacol Toxicol 1997;80:111-7.
  • van Montfoort JE, Hagenbuch B, Groothuis GM, Koepsell H, Meier PJ, Meijer DK. Drug uptake sys- tems in liver and kidney. Curr Drug Metab 2003;4:185-211.
  • Maniccia-Bozzo E, Espiritu MB, Singh G. Differential effects of cisplatin on mouse hepatic and renal mitochondrial DNA. Mol Cell Biochem 1990;94:83-8.
  • Stewart DJ, Benjamin RS, Luna M, Feun L, Caprioli R, Seifert W, et al. Human tissue distribution of plat- inum after cis-diamminedichloroplatinum. Cancer Chemother Pharmacol 1982;10:51-4.
  • Tamura J, Tanaka J, Fujita K, Yoshida M, Kasamatsu T, Arii S, et al. Effect of anticancer agents on cell cycle of regenerating hepatocytes in rats. J Surg Res 1992;53:218-26.
  • Singh G. A possible cellular mechanism of cisplatin- induced nephrotoxicity. Toxicology 1989;58:71-80.
  • Brady HR, Zeidel ML, Kone BC, Giebisch G, Gullans SR. Differential actions of cisplatin on renal proximal tubule and inner medullary collecting duct cells. J Pharmacol Exp Ther 1993;265:1421-8.
  • Kharbangar A, Khynriam D, Prasad SB. Effect of cis- platin on mitochondrial protein, glutathione, and succinate dehydrogenase in Dalton lymphoma-bear- ing mice. Cell Biol Toxicol 2000;16:363-73.
  • Khynriam D, Prasad SB. Changes in glutathione- related enzymes in tumor-bearing mice after cis- platin treatment. Cell Biol Toxicol 2002;18:349-58.
  • Farber JL, Gerson RJ. Mechanisms of cell injury with hepatotoxic chemicals. Pharmacol Rev 1984;36(2 Suppl):71S-75S.
  • el-Shazly MO, Afify MM, el-Dieb MK. Histopathological study into side-effect toxicity of some drugs used in treatment of cancer. Arch Exp Veterinarmed 1989;43:319-26.
  • Guinee DG Jr, van Zee B, Houghton DC. Clinically silent progressive renal tubulointerstitial disease dur- ing cisplatin chemotherapy. Cancer 1993;71:4050-4.
  • Marin JJ, Herrera MC, Palomero MF, Macias RI, Monte MJ, El-Mir MY, et al. Rat liver transport and biotransformation of a cytostatic complex of bis- cholylglycinate and platinum (II). J Hepatol 1998;28:417-25.
  • Kramer W, Wess G, Schubert G, Bickel M, Girbig F, Gutjahr U, et al. Liver-specific drug targeting by cou- pling to bile acids. J Biol Chem 1992;267:18598-604.
  • Bengochea L, Ghanem C, Perazzo JC, Ghisolfi C, Marabotto L, Acevedo C, et al. Drug glucuronida- tion and hepatic lipid microsomal membrane profile in cholestatic rats followed paracetamol intoxica- tion. Pharmacol Res 1999;40:369-76.
  • Blasiak J, Kowalik J. Protective action of vitamin C against DNA damage induced by selenium-cisplatin conjugate. Acta Biochim Pol 2001;48:233-40.

E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi

Yıl 2005, Cilt: 2005 Sayı: 3, 124 - 131, 01.03.2005

Öz

Amaç: Bu çalışmada, bir antineoplastik ajan olan cisplatinin kronik uygulandığında yol açtığı karaciğer hasarı ve bu hasara karşı E ve C vitaminlerinin ne ölçüde koruma sağlayacağı histolojik olarak incelendi. Çalışma Planı: Çalışmada, 24 adet Wistar albino cinsi erkek sıçan altışarlı dört gruba ayrıldı. Kontrol grubu dışındaki (grup 1) deneklere üç ay boyunca, ayda bir kez 5 mg/kg cisplatin intravenöz yolla verildi. Grup 3 ve 4'teki deneklere ise ayrıca, her gün intramusküler yolla sırasıyla 5 mg/kg E vitamini ve 8 mg/kg C vitamini verildi. Deney süresinin sonunda, tüm deneklerin karaciğer materyalleri alınarak ışık ve elektron mikroskobisi ile incelendi. Bulgular: Kontrol grubu deneklerde normal yapıda karaciğer dokusu gözlendi. İkinci grupta Remak kordonları nda düzensizleşme, V. centrolobularis'e yakın sinüzoidlerde genişleme ile birlikte bazal membranlarda kalınlaşma, portal sahalarda ise lenfosit infiltrasyonu görüldü. Üçüncü grupta morfolojik hasarı n büyük oranda azaldığı, çoğu portal sahada lenfosit infiltrasyonunun ortadan kalktığı; dördüncü grupta ise düzelmenin daha da belirginleşerek portal saha infiltrasyon bölge sayısının hem seyreldiği hem de infiltrasyon hücre sayısının çok azaldığı görüldü. Sonuç: Farklı özelliklere sahip antioksidanların cisplatinin hepatotoksisitesinin azalmasına yardımcı olarak klinik uygulamaya katkıda bulunacağı sonucuna varıldı.

Kaynakça

  • Naziroglu M, Karaoglu A, Aksoy AO. Selenium and high dose vitamin E administration protects cis- platin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 2004;195:221-30.
  • Antunes LM, Darin JD, Bianchi Nde L. Effects of the antioxidants curcumin or selenium on cisplatin- induced nephrotoxicity and lipid peroxidation in rats. Pharmacol Res 2001;43:145-50.
  • Cersosimo RJ. Hepatotoxicity associated with cis- platin chemotherapy. Ann Pharmacother 1993;27:438-41.
  • Liu J, Liu Y, Habeebu SS, Klaassen CD. Metallothionein (MT)-null mice are sensitive to cis- platin-induced hepatotoxicity. Toxicol Appl Pharmacol 1998;149:24-31.
  • Imamura Y, Hirata M, Takada H, Otagiri M. Acetohexamide reductase activities in liver micro- somes and cytosol of cisplatin-treated male rats: cis- platin indirectly modulates the microsomal enzyme activity. Res Commun Mol Pathol Pharmacol 1996;94:203-10.
  • Stewart DJ, Mikhael NZ, Nanji AA, Nair RC, Kacew S, Howard K, et al. Renal and hepatic concentrations of platinum: relationship to cisplatin time, dose, and nephrotoxicity. J Clin Oncol 1985;3:1251-6.
  • Zicca A, Cafaggi S, Mariggio MA, Vannozzi MO, Ottone M, Bocchini V, et al. Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats. Eur J Pharmacol 2002;442:265-72.
  • Welters MJ, Fichtinger-Schepman AM, Baan RA, Jacobs-Bergmans AJ, Kegel A, van der Vijgh WJ, et al. Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum con- tent, DNA adduct levels and drug sensitivity in vitro and in vivo. Br J Cancer 1999;79:82-8.
  • Chu G. Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. J Biol Chem 1994;269:787-90.
  • Capel ID, Leach D, Dorrell HM. Vitamin E retards the lipoperoxidation resulting from anticancer drug administration. Anticancer Res 1983;3:59-62.
  • el Daly ES. Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cis- platin-induced toxicity in rats. J Pharm Belg 1998;53:87-93; discussion 93-5.
  • Sadzuka Y, Shoji T, Takino Y. Effect of cisplatin on the activities of enzymes which protect against lipid peroxidation. Biochem Pharmacol 1992;43:1872-5.
  • Ramanathan K, Shila S, Kumaran S, Panneerselvam C. Ascorbic acid and alpha-tocopherol as potent modulators on arsenic induced toxicity in mitochon- dria. J Nutr Biochem 2003;14:416-20.
  • Senyelli B. İntraperitoneal mitomisin C ile geliştiri- len deneysel kolitte antioksidanların etkisi. [Uzman- lık Tezi]. Edirne: Trakya Üniversitesi Tıp Fakültesi İç Hastalıkları Anabilim Dalı; 1999.
  • Murray RK, Granner DK, Mayes PA, Rodwell VW, editors. Yağda çözünen vitaminlerin yapı ve fonksiyonu. In: Harper’in biyokimyası (Harper's biochemistry. 22nd ed. Norwalk, CT: Appleton and Lange; 1990.) Çeviri editörü: Menteş G, Ersöz B. İstanbul: Barış Kitabevi; 1993. s. 711-2.
  • Padh H. Vitamin C: newer insights into its biochem- ical functions. Nutr Rev 1991;49:65-70.
  • Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 1999;13:1007-24.
  • Demir R, editör. Histolojik boyama teknikleri başvuru kitabı. Ankara: Palme yayıncılık; 2001.
  • Gabe M. Les principes généraux de la technique his- tologique. Paris: Masson et Cie; 1968. p. 10-30.
  • Hayat MA. Principles and techniques of electron microscopy: biological applications. 1st ed. USA: Van Nostrand Reinhold Company; 1970.
  • Wang K, Shindoh H, Inoue T, Horii I. Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines. J Toxicol Sci 2002;27:229-37.
  • Poklis A. Toxic responses of the liver. In: Klaassen CD, editor. Casarett & doull’s toxicology. Fifth ed: New York: The McGraw Hill Co; 1996. p. 403-15.
  • Briz O, Serrano MA, Rebollo N, Hagenbuch B, Meier PJ, Koepsell H, et al. Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis- diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells. Mol Pharmacol 2002;61:853-60.
  • Villanueva GR, Mendoza ME, el-Mir MY, Monte MJ, Herrera MC, Marin JJ. Effect of bile acids on hepato- biliary transport of cisplatin by perfused rat liver. Pharmacol Toxicol 1997;80:111-7.
  • van Montfoort JE, Hagenbuch B, Groothuis GM, Koepsell H, Meier PJ, Meijer DK. Drug uptake sys- tems in liver and kidney. Curr Drug Metab 2003;4:185-211.
  • Maniccia-Bozzo E, Espiritu MB, Singh G. Differential effects of cisplatin on mouse hepatic and renal mitochondrial DNA. Mol Cell Biochem 1990;94:83-8.
  • Stewart DJ, Benjamin RS, Luna M, Feun L, Caprioli R, Seifert W, et al. Human tissue distribution of plat- inum after cis-diamminedichloroplatinum. Cancer Chemother Pharmacol 1982;10:51-4.
  • Tamura J, Tanaka J, Fujita K, Yoshida M, Kasamatsu T, Arii S, et al. Effect of anticancer agents on cell cycle of regenerating hepatocytes in rats. J Surg Res 1992;53:218-26.
  • Singh G. A possible cellular mechanism of cisplatin- induced nephrotoxicity. Toxicology 1989;58:71-80.
  • Brady HR, Zeidel ML, Kone BC, Giebisch G, Gullans SR. Differential actions of cisplatin on renal proximal tubule and inner medullary collecting duct cells. J Pharmacol Exp Ther 1993;265:1421-8.
  • Kharbangar A, Khynriam D, Prasad SB. Effect of cis- platin on mitochondrial protein, glutathione, and succinate dehydrogenase in Dalton lymphoma-bear- ing mice. Cell Biol Toxicol 2000;16:363-73.
  • Khynriam D, Prasad SB. Changes in glutathione- related enzymes in tumor-bearing mice after cis- platin treatment. Cell Biol Toxicol 2002;18:349-58.
  • Farber JL, Gerson RJ. Mechanisms of cell injury with hepatotoxic chemicals. Pharmacol Rev 1984;36(2 Suppl):71S-75S.
  • el-Shazly MO, Afify MM, el-Dieb MK. Histopathological study into side-effect toxicity of some drugs used in treatment of cancer. Arch Exp Veterinarmed 1989;43:319-26.
  • Guinee DG Jr, van Zee B, Houghton DC. Clinically silent progressive renal tubulointerstitial disease dur- ing cisplatin chemotherapy. Cancer 1993;71:4050-4.
  • Marin JJ, Herrera MC, Palomero MF, Macias RI, Monte MJ, El-Mir MY, et al. Rat liver transport and biotransformation of a cytostatic complex of bis- cholylglycinate and platinum (II). J Hepatol 1998;28:417-25.
  • Kramer W, Wess G, Schubert G, Bickel M, Girbig F, Gutjahr U, et al. Liver-specific drug targeting by cou- pling to bile acids. J Biol Chem 1992;267:18598-604.
  • Bengochea L, Ghanem C, Perazzo JC, Ghisolfi C, Marabotto L, Acevedo C, et al. Drug glucuronida- tion and hepatic lipid microsomal membrane profile in cholestatic rats followed paracetamol intoxica- tion. Pharmacol Res 1999;40:369-76.
  • Blasiak J, Kowalik J. Protective action of vitamin C against DNA damage induced by selenium-cisplatin conjugate. Acta Biochim Pol 2001;48:233-40.
Toplam 39 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Bölüm Makaleler
Yazarlar

Yeter Topçu Tarladaçalışır Bu kişi benim

Müberra Uygun Bu kişi benim

Meryem Akpolat Bu kişi benim

Yeşim Hülya Uz Bu kişi benim

Yayımlanma Tarihi 1 Mart 2005
Yayımlandığı Sayı Yıl 2005 Cilt: 2005 Sayı: 3

Kaynak Göster

APA Tarladaçalışır, Y. T., Uygun, M., Akpolat, M., Uz, Y. H. (2005). E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi. Balkan Medical Journal, 2005(3), 124-131.
AMA Tarladaçalışır YT, Uygun M, Akpolat M, Uz YH. E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi. Balkan Medical Journal. Mart 2005;2005(3):124-131.
Chicago Tarladaçalışır, Yeter Topçu, Müberra Uygun, Meryem Akpolat, ve Yeşim Hülya Uz. “E Ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi”. Balkan Medical Journal 2005, sy. 3 (Mart 2005): 124-31.
EndNote Tarladaçalışır YT, Uygun M, Akpolat M, Uz YH (01 Mart 2005) E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi. Balkan Medical Journal 2005 3 124–131.
IEEE Y. T. Tarladaçalışır, M. Uygun, M. Akpolat, ve Y. H. Uz, “E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi”, Balkan Medical Journal, c. 2005, sy. 3, ss. 124–131, 2005.
ISNAD Tarladaçalışır, Yeter Topçu vd. “E Ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi”. Balkan Medical Journal 2005/3 (Mart 2005), 124-131.
JAMA Tarladaçalışır YT, Uygun M, Akpolat M, Uz YH. E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi. Balkan Medical Journal. 2005;2005:124–131.
MLA Tarladaçalışır, Yeter Topçu vd. “E Ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi”. Balkan Medical Journal, c. 2005, sy. 3, 2005, ss. 124-31.
Vancouver Tarladaçalışır YT, Uygun M, Akpolat M, Uz YH. E ve C Vitaminlerinin Cisplatin Hepatotoksisitesini Önlemedeki Etkilerinin Histolojik Olarak İncelenmesi. Balkan Medical Journal. 2005;2005(3):124-31.