Zingerone Attenuates Methotrexate-Induced Hepatotoxicity in Rats

Abstract

Background: Methotrexate (MTX) is mainly used for the chemotherapy of different types of malignancy and some autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease. The MTX application is limited by its severe side effects, including several types of hepatic injury. Objectives: In this study, we decided to evaluate if zingerone (the main constituent of ginger) can reduce the hepatic side effects of MTX. Methods: Thirty-five rats were divided into five groups: Control group receiving normal saline (N/S), once daily, by gavage, for 10 days, and N/S intraperitoneally (i.p.), a single dose on the ninth day; Methotrexate (MTX) group receiving N/S, once daily, by gavage, for 10 days, and MTX (i.p.), a single dose (20 mg/kg) on the ninth day; Groups 3 (ZG25), 4 (ZG50), and 5 (ZG100) receiving zingerone (25, 50, and 100 mg/kg, respectively), once daily, by gavage, for 10 days, and MTX (i.p.), a single dose (20 mg/kg) on the ninth day. Results: The results showed a significant decrease in serum AST, ALT, and ALP, as well as the hepatic content of MDA, NO, PC, TNF-α, and IL-1β, in the ZG groups compared with the MTX group. The activity of SOD, CAT, and GPX, as well as the hepatic content of GSH, showed a significant increase in the ZG groups compared with the MTX group. Histopathological improvement in the hepatic tissue of ZG groups compared with the MTX group confirmed all other findings. Conclusions: It is concluded that zingerone can improve hepatic injury induced by MTX in rats regarding the redox system features, inflammation, and histological changes. This can make humans hopeful for using Ginger in the future for attenuating the hepatic side effects of MTX when used chronically.

Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death

“…Increased oxidative damage of the liver has been described as an important primary mechanism leading to the development of MTX-induced hepatotoxicity [ 21 , 22 , 27 ]. In hepatocytes, the enzyme folylpolyglutamyl synthetase converts MTX to MTX polyglutamates by adding up to six glutamate residues to MTX and increasing its intracellular retention, which triggers ROS overproduction and oxidative damage in liver tissue [ 13 , 15 ].…”

“…These findings were supported by previous studies where MTX injection was associated with increased apoptosis in the liver [ 21 , 22 , 53 ]. The most likely trigger of MTX-induced apoptosis is sustained ROS production after MTX exposure that culminates in the dissipation of mitochondrial membrane potential and cytochrome c release which ultimately induces the execution phase of caspase-3-dependent apoptosis [ 15 , 25 , 27 ]. Thus, prevention of the MTX-induced ROS overproduction and NF-κB activation can attenuate apoptosis and consequently protect against liver injury and dysfunction induced by MTX.…”

“…Extensive evidence suggests that using natural substances with antioxidant and anti-inflammatory characteristics can effectively treat MTX-induced liver injuries [ 25 , 26 , 27 , 28 ]. Plants are considered as one of the main sources of medically relevant active compounds, including polyphenols.…”