DX is a chemotherapeutic antibiotic that is frequently used in cancer treatment
17. Hepatotoxicity is a serious complication of DX therapy
18. A study reported increased AST and ALT levels as an indicator of liver damage from DX administration
19. The results obtained in this current study showed that serum AST and ALT levels increased and Albumin levels decreased due to DX administration. These data are consistent with other recent studies
20,21. In addition, a study reported that DX administration caused histopathological changes in the liver tissue
22. In this study, in the liver tissue of DX application; It has been observed that it causes sinusoidal dilatation, vacuolization, mononuclear cell infiltration, degeneration of hepatocytes, hemorrhagic areas and vascular congestion. Some studies have similarly reported that DX chemotherapy may cause histopathological changes in liver tissue
2,3,20. However, in this study, it was determined that these biochemical and histopathological changes caused by DX were significantly reduced/mitigated with RSV (5mg/kg/day) treatment.
Apoptosis plays an important role in DX induced toxicity 23. Apoptosis is an organized process involving cellular proteins and signaling pathways. Apoptotic proteins are divided into two groups according to their roles as anti-apoptotic and pro-apoptotic. BcL2 family proteins, localized in the outer membrane of mitochondria, function as both anti-apoptotic (BcL2, etc.) and proapoptotic (Bax, etc.) 24. A recent study reported that DX administration caused an increase in Bax expression and a 60.6% decrease in BcL2 mRNA expression 1. Another study reported that in the liver, in contrast to the control group, the fluorescence intensity of BcL2 decreased significantly in the DX group, whereas the fluorescence intensity of Bax increased clearly in the liver. However, the same study revealed that the ratio of Bax/BcL2 protein analyzed by Western blot technique in the DX group was greatly increased 21. In this current study, it was observed that DX administration caused an increase in Bax immunoreactivity in liver tissue, while BcL2 immunoreactivity was significantly decreased. Consistent with the studies, it was determined that the Bax/BcL2 ratio increased in DX-induced hepatotoxicity. It was observed that these DX-induced apaptotic protein immunoreactivities changes were significantly alleviated by RSV (5mg/kg/day) treatment. In addition, immunohistochemistry analyzes of Casp3 immunoreactivity in studies revealed that the percentages of Casp3 positive areas increased significantly with DX application 21. Similarly, this current study showed that DX administration significantly increased Casp3 immunoreactivity in liver tissue compared to the control group. In line with these data, a study showed that Casp3 immunoreactivity and the number of TUNEL-positive cells in liver tissue were significantly increased in the DX group compared to the control group 6. In addition, in this current study, it was determined that RSV (5mg/kg/day) treatment significantly reduced the DX-induced increased Casp3 immunoreactivity.
In this current study, it was determined that 1 mg/kg RSV administration was not as effective as 5 mg/kg RSV in improving DX-induced hepatotoxicity. These results showed that RSV treatment may have a dose-dependent hepatoprotective effect. Similarly, a recent study reported that low doses of RSV are beneficial in chronic treatments, while high doses of RSV treatment are needed for acute treatment 25. This suggests that the failure to achieve the desired result with 1 mg/kg RSV treatment may be about the duration of the study. In addition, in a study conducted on diabetic rats, the antidiabetic effects of 1, 5 and 10 mg/kg RSV treatment were compared, and it was reported that the best results were obtained with 5 mg/kg RSV treatment 15. Consistent with these data, it was observed that 5 mg/kg/day RSV treatment reduced/attenuated the DX-induced biochemical and histopathological changes in liver tissue. However, RSV (5 mg/kg/day) decreased Bax/BcL2 ratio and Casp3 immunoreactivity to inhibit cell apoptosis against DX-induced hepatotoxicity. Therefore, the data obtained in this study indicate that 5 mg/kg/day RSV has an important role in preventing apoptosis through Bax/BcL2 modulation.
In conclusion, in this study, liver tissue damage was determined biochemically, histopathologically and immunohistochemically in rats exposed to DX, a chemotherapeutic drug widely used in the clinic. On the other hand, the protective effect of RSV treatment was determined by liver function tests, apoptotic proteins immunoreactivities and histopathological examination of tissue degeneration. The data obtained from this study reveal that 5 mg/kg/day RSV treatment may provide an antiapoptotic effect against DX-induced liver injury.
Acknowledgment: The authors thank dear Assoc Prof Tuncay KULOGLU for their contribution to this study.