Comparison of the acute and cumulative dose administrations in doxorubicin-induced hepatotoxicity via evaluation of the histopathological changes and inflammation in rats

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic, and it is widely used as an antineoplastic agent in the treatment of many cancer types such as sarcoma, acute lymphoblastic leukemia and as well as breast and liver cancers. However, it may lead to hepatotoxicity when administered chronically or in a high dose. The aim of this study is to determine dose-dependent effects of DOX in rat liver tissue. For this purpose, thirty male Wistar albino rats were divided into three groups: Group I as Control; Group II: Chronic DOX administered cumulative dose of DOX (2 mg/kg, twice in a week, total 20 mg/kg, i.p); Groups III: Acute DOX group administered single dose DOX (15 mg/kg, i.p) at the 20th day of the experiment. At the end of the 30th day, animals were sacrificed, and liver tissues were extracted for histopathological and immunohistochemical evaluation. Sections were stained with hematoxylin and eosin to evaluate the histopathological changes and TNF- and IL-6 expressions were detected by immunohistochemical staining. Both chronic and acute administrations of DOX triggered significant liver damage. However, it was observed that liver damage induced by acute single dose DOX administrations were higher than those cumulative chronic DOX administrations. TNF- and IL-6 immunoreactivity was significantly increased in both Chronic DOX group and Acute DOX group compared to Control group. However, immunoreactivity of TNF- was substantially higher in the Acute DOX group compared to Chronic DOX group. These results demonstrated that acute administrations of DOX relatively induce serious liver damage and inflammatory response when compared to cumulative chronic administrations. In conclusion, it may be advisable to increase studies on the use of acute doses in combination with protective anti-inflammatory agents.

Keywords

• doxorubicin
• hepatotoxicity
• inflammation
• liver damage

Abstract

Doksorubisin (DOX) göğüs kanseri ve hepatosellüler karsinomların yanı sıra sarkoma ve akut lenfoblastik lösemi gibi birçok kanser türünün tedavisinde de antineoplastik ajan olarak yaygın şekilde kullanılan bir antrasiklin antibiyotiktir. Ancak kronik veya yüksek dozlarda uygulandığında hepatotoksisiteye neden olabilmektedir. Bu çalışmanın amacı, doksorubisinin sıçan karaciğer dokularındaki doz bağımlı etkisinin belirlenmesidir. Bu amaçla, 30 adet Wistar albino ırkı sıçan 3 gruba ayrıldı: Grup I: Kontrol grubu, Grup II: Kümülatif dozda (2 mg/kg, haftada iki defa, toplam 20 mg/kg, i.p.) doksorubisin uygulanan Kronik DOX grubu, Grup III: Deneyin 20. günü tek doz (15 mg/kg, i.p.) doksorubisin uygulanan Akut DOX grubu. 30. günün sonunda, deney hayvanları sakrifiye edildi ve histopatolojik ve immünohistokimyasal analizler için karaciğer dokuları alındı. Karaciğer dokularından elde edilen kesitler hematoksilen-eozin ile boyandı ve dokulardaki TNF- ve IL-6 ekspresyonları immünohistokimyasal boyamalar ile belirlendi. Hem kronik hem de akut doksorubisin uygulamaları karaciğer dokularında ciddi bir hasara neden oldu. Bununla birlikte, akut tek doz doksorubisin uygulanan gruptaki karaciğer hasarının kümülatif dozda doksorubisin uygulanan gruptakinden daha fazla olduğu gözlendi. TNF- ve IL-6 ekspresyonlarının hem Kronik DOX grubunda hem de Akut DOX grubunda Kontrol grubu ile karşılaştırıldığında anlamlı bir şekilde arttığı belirlendi. Ancak, Akut DOX grubundaki TNF- immunoreaktivitesinin Kronik DOX grubuna göre anlamlı bir şekilde arttığı görüldü. Bu sonuçlar, akut tek doz olarak uygulanan doksorubisinin sıçan karaciğer dokularında kümülatif dozlara göre daha ciddi bir karaciğer hasarı ve inflamatuvar yanıt meydana getirdiğini göstermektedir. Sonuç olarak, doksorubisinin akut uygulamalarının koruyucu anti-inflamatuvar ajanlarla kombinasyon halinde kullanımına ilişkin çalışmaların artırılması tavsiye edilebilir.

Keywords

• Doksorubisin
• hepatotoksisite
• enflamasyon
• karaciğer hasarı

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