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Updated: Mar 23, 2026
Inducing Acute Liver Injury in Rats via Carbon Tetrachloride CCl4 Exposure Through an Orogastric Tube
Published on: April 28, 2020
New mechanism in the modulation of carbon tetrachloride hepatotoxicity in rats using different natural antioxidants
Nouf Mohamed Al-Rasheed1, Laila Mohamed Fadda1, Hanaa Mahmoud Ali2,3
1a Department of Pharmacology , Faculty of Pharmacy, King Saud University , Riyadh , Kingdom of Saudi Arabia .
Abstract:
Transforming growth factor-β (TGF-β1) enhances the expression of apoptosis induced by certain cytokines and oncogenes. Activation of small mother against decapentaplegic (Smads) by TGF-β results in fibrotic, apoptotic processes. PI-3/AKT focal adhesion kinase-phosphatidylinositol3-kinase (AKT), the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3) pathways are influence in COX-2 and VEGF-stimulating pathways. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. The objective of this study is to examine whether silymarin alone or in combination with vitamin E and/or curcumin plays a modulatory role against MAPK, STAT3, AKT, Smad-2 and TGF-β protein expressions that produced apoptotic damage in rat's liver by the administration of carbon tetrachloride (CCl4). The results of the present work revealed that CCl4-induced an elevation of serum alanine aminotransferase (ALT) with concomitant increase in MAPK, STAT3, AKT, Smad-2 and TGF-β hepatic protein expression, administration of silymarin alone down regulates these expressions. Treatment with vitamin E and/or curcumin along with silymarin produced best results in this concern. On the other hand, Nrf2 protein expression was down regulated by CCl4 whereas concurrent treatment with vitamin E and/or curcumin along with silymarin increased this expression. It was concluded that CCl4-induced protein expression of apoptotic and fibenorgenic factors. Whereas administration of silymarin alone or in combination with vitamin E and/or curcumin plays a modulatory role against the previous aforementioned apoptotic factors expressions. The use of vitamin E and/or curcumin potentiates the anti-apoptotic action of silymarin. So this combination can be used as hepatoprotective agent against other hepatotoxic substances.
Insights
Silymarin, vitamin E, and curcumin protect the liver from carbon tetrachloride (CCl4) damage by reducing apoptotic factors and increasing antioxidant Nrf2 expression. This combination shows potent hepatoprotective effects.
Area of Science:
- Hepatology
- Biochemistry
- Molecular Biology
Background:
- Transforming growth factor-β (TGF-β1) signaling pathways, including Smads, AKT, MAPK, and STAT3, are implicated in apoptosis and fibrosis.
- NF-E2-related factor-2 (Nrf2) is a key regulator of antioxidant and detoxification genes in the liver.
- Carbon tetrachloride (CCl4) is a known hepatotoxin that induces liver damage through oxidative stress and apoptosis.
Purpose of the Study:
- To investigate the modulatory effects of silymarin, alone or in combination with vitamin E and/or curcumin, on CCl4-induced liver injury.
- To assess the impact of these treatments on key apoptotic and fibrogenic signaling pathways (MAPK, STAT3, AKT, Smad-2, TGF-β) and the antioxidant factor Nrf2.
Main Methods:
- Rats were administered CCl4 to induce liver damage.
- Treatment groups received silymarin alone, vitamin E alone, curcumin alone, or combinations thereof.
- Hepatic protein expressions of MAPK, STAT3, AKT, Smad-2, TGF-β, and Nrf2 were analyzed.
Main Results:
- CCl4 administration significantly increased serum ALT levels and hepatic expressions of MAPK, STAT3, AKT, Smad-2, and TGF-β.
- Silymarin alone downregulated these pro-apoptotic and fibrogenic factors.
- Combinations of silymarin with vitamin E and/or curcumin demonstrated the most significant protective effects, further downregulating apoptotic markers and increasing Nrf2 expression.
Conclusions:
- CCl4 induces liver damage by upregulating apoptotic and fibrogenic factors.
- Silymarin, especially when combined with vitamin E and/or curcumin, exhibits significant hepatoprotective effects by modulating these pathways.
- The combination therapy potentiates silymarin's anti-apoptotic action, suggesting its potential as a hepatoprotective agent against various hepatotoxins.
