Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3β Pathway in In Vivo and In Silico Experimental Models
Abstract: Background: 5-fluorouracil (5-FU) is a widely used, highly effective chemotherapeutic
agent. However, its therapeutic efficacy is often limited by associated adverse effects, with hepatotoxicity
being frequently reported with 5-FU therapy. Thymol is a monoterpene found in thyme
(Thymus vulgaris L., Lamiaceae) and is known for its antioxidant, anti-apoptotic, and anticancer activities.
This study aimed to explore the hepatoprotective activity of thymol against 5-FU-induced
liver injury. Methods: Rats received two intraperitoneal doses of 5-FU (150 mg/kg) either alone
or in combination with thymol at doses of 60 mg/kg or 120 mg/kg. Liver enzymes, oxidative
stress, and apoptotic markers, in addition to histopathological changes, were assessed. Results:
5-FU induced marked liver injuries as evidenced by elevated liver enzymes and histopathological
changes, in addition to abnormalities of oxidative and apoptotic markers. The administration of
thymol ameliorated the 5-FU-induced oxidative damage through increasing hepatic antioxidants and
lowering lipid peroxidation. Apoptotic response markers such as Bax, Bcl-2, Bax/Bcl-2 ratio, and
PARP were also improved. Furthermore,Western blotting analysis showed that thymol modulated
the 5-FU-induced changes in the expression of Akt/GSK-3β and p44/42 MAPK (ERK1/2) signaling
pathways. Conclusions: Our research is the first to shed light on thymol’s potential protective effect
against 5-FU- induced hepatotoxicity by inhibiting oxidative and apoptotic pathways and modulating
the Akt/ GSK-3β as well as p44/42 MAPK (ERK1/2) signaling pathways.
Abstract: Background: 5-fluorouracil (5-FU) is a widely used, highly effective chemotherapeutic
agent. However, its therapeutic efficacy is often limited by associated adverse effects,…