Combined the Vitamin E and Trimetazidine Therapy Ameliorate Hepatic Injury from Doxorubicin Administration in Mice

Abstract

Background: Chemotherapy-related hepatotoxicity may weaken the patient so much that the desired course of treatment is not achieved. Therefore, it is better to combine antioxidant therapy with doxorubicin (DOX). Vitamin E (Vit E) or trimetazidine (TMZ) were administered as antioxidants in this study. Objectives: In this study, the reparative effects of Vit E and TMZ administration on DOX-induced hepatotoxicity were investigated. Methods: Animals included 25 male BALB/c mice divided into five groups (n = 5). The groups included sham: No administration; DOX: An accumulative dose of 25 mg/kg/i.p. in the days 12, 13 and 14 of experiment; Vit E: Twice administration of 200 IU/kg PO for 10 days followed by DOX therapy; TMZ: Ten mg/kg/day for 10 days followed by DOX therapy; and Vit E-TMZ: Administration of Vit E and TMZ for 10 days followed by DOX therapy. On day 15, blood and liver tissue samples were collected after euthanasia. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels were measured to assess the severity of liver lesions. Half of the liver tissue was examined for histopathology. The other half for the liver was examined for total antioxidant capacity (TAC) and malondialdehyde measurements, as well as for examining the expression of TNFα (inflammation) and Bax (apoptosis) genes. Histopathological scoring for necrosis, vacuolar degeneration, and inflammation was from 0 to 3 based on the severity of the lesions. Results: The DOX group had the most liver tissue problems. In some areas, necrosis, vacuolation, and inflammation were seen. Liver-related enzymes such as GGT, ALT and AST were increased in DOX compared the others (P < 0.0001). The liver TAC level was only significant between the DOX group and the Vit E-TMZ group (P < 0.01). The liver MDA levels were highest in the DOX group and were significant with sham (P < 0.0001), Vit E (P < 0.05) and the other (P < 0.01) groups. In addition, TNF-α and Bax genes expression appeared much higher in the DOX group and were significant with sham (P < 0.0001) the other groups than normal. Regarding the other groups, it should be noted that in the Vit E or TMZ group, the amount of liver damage, liver-related enzymes, and TNFα and Bax expression increased compared to the DOX group but was not lower than the sham group. On the other hand, the Vit E-TMZ group showed the best results in terms of the significance of reducing damage, inflammation levels, and apoptosis. Conclusions: The simultaneous use of Vit E and TMZ reduces microscopic DOX induced liver lesions. This combination had effective reducing effects on the inflammatory factor TNF-alpha and the number of apoptotic cells after DOX administration.