Naringenin Regulates Doxorubicin-Induced Liver Dysfunction: Impact on Oxidative Stress and Inflammation

Abstract

Doxorubicin (Dox) is an operational and largely used anticancer drug, used to treat an array of malignancies. Nonetheless, its beneficial use is constrained due to its renal and hepatotoxicity dose dependently. Numerous research findings favor the use of antioxidants may impact Dox-induced liver injury/damage. In the current study, Wistar rats were given naringenin (50 and 100 mg/kg b.wt.) orally for 20 days as prophylactic dose, against the hepatotoxicity induced by single intraperitoneal injection of Dox (20 mg/kg b.wt.). Potency of naringenin against the liver damage caused by Dox was assessed by measuring malonyl aldehyde (MDA) as a by-product of lipid peroxidation, biochemical estimation of antioxidant enzyme system, reactive oxygen species (ROS) level, and inflammatory mediators. Naringenin-attenuated ROS production, ROS-induced lipid peroxidation, and replenished reduced antioxidant armory, namely, catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). Naringenin similarly diminished expression of Cox-2 and levels of NF-κB and other inflammatory molecules induced by the Dox treatment. Histology added further evidence to the defensive effects of naringenin on Dox-induced liver damage. The outcomes of the current study reveal that oxidative stress and inflammation are meticulously linked with Dox-triggered damage, and naringenin illustrates the potential effect on Dox-induced hepatotoxicity probably through diminishing the oxidative stress and inflammation.

Keywords: NF-κB; doxorubicin; hepatotoxicity; naringenin; reactive oxygen species.

Figure 1

Effect of naringenin and doxorubicin treatment on ROS levels. In Dox-treated group-II, the reactive oxygen species (ROS) level was increased significantly (*** p < 0.001) as compared to the control group -I. Treatment with naringenin (50 and 100 mg/kg b. wt.) significantly attenuated ROS levels in group III (^# p < 0.05) and group IV (^### p < 0.01) as compared to group II.

Figure 2

Effect of naringenin and doxorubicin treatment on malonyl aldehyde (MDA) levels. In Dox-treated group-II, the MDA level was increased significantly (*** p < 0.001) as compared to the control group-I. Treatment with naringenin (50 and 100 mg/kg b. wt.) significantly attenuated MDA levels in group III (^# p < 0.05) and group IV (^### p < 0.01) as compared to group II.

Figure 3

Effect of naringenin and doxorubicin on nitrite levels. In Dox-treated group-II, the nitrite levels were significantly increased (*** p < 0.001) as compared to the control group-I. Treatment with naringenin significantly (50 and 100 mg/kg b. wt.) attenuated nitrite levels in group III (^# p < 0.05) and group IV (^### p < 0.001) as compared to group-II.

Figure 4

Effect of naringenin treatment on Dox-induced pathological changes in liver. Photomicrographs of H&E staining of histological sections of liver depicting different experimental groups, group I indicate normal histoarchitecture of liver sections. Group II shows extensive disintegration of normal architecture in the Dox-treated group. In groups III and IV, naringenin treatment showed protection against naringenin-induced pathological changes. Both the doses of naringenin maintained the integrity of central vein and hepatocytes. Magnification: 40×.

Figure 5

Effect of naringenin treatment on Cox-2 expression. Photomicrographs of hepatic sections depicting immunohistochemical analyses, brown color indicates specific immunostaining of Cox-2 and light blue color indicates counter staining by nuclear hematoxylin. The hepatic section of Dox-treated group II has more Cox-2 immunopositive staining as indicated by brown color as compared to the control group I, whereas treatment of naringenin (50 and 100 mg/kg b. wt.) in groups III and IV reduced Cox-2 immunostaining as compared to group II. Original magnification: 40×.