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Updated: May 5, 2026
Inducing Acute Liver Injury in Rats via Carbon Tetrachloride CCl4 Exposure Through an Orogastric Tube
Published on: April 28, 2020
Protective effects of diallyl disulfide on carbon tetrachloride-induced hepatotoxicity through activation of Nrf2
In-Chul Lee1, Sung-Hwan Kim, Hyung-Seon Baek
1Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chonnam National University, Gwangju, 500-757, Republic of Korea.
Abstract:
This study was conducted to investigate the potential effects of diallyl disulfide (DADS) on carbon tetrachloride (CCl4 )-induced acute hepatotoxicity and to determine the molecular mechanisms of protection offered by DADS in rats. DADS was administered orally at 50 and 100 mg/kg/day once daily for 5 consecutive days prior to CCl4 administration. The single oral dose of CCl4 (2 mL/kg) caused a significant elevation in serum aspartate and alanine aminotransferase activities, which decreased upon pretreatment with DADS. Histopathological examinations showed extensive liver injury, characterized by extensive hepatocellular degeneration/necrosis, fatty changes, inflammatory cell infiltration, and congestion, which were reversed following pretreatment with DADS. The effects of DADS on cytochrome P450 2E1 (CYP2E1), the major isozyme involved in CCl4 bioactivation, were also investigated. DADS pretreatment resulted in a significant decrease in CYP2E1 protein levels in dose-dependent manner. In addition, CCl4 caused a decrease in protein level of cytoplasmic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2 concurrent with downregulation of detoxifying phase II enzymes and a decrease in antioxidant enzyme activities. In contrast, DADS prevented the depletion of cytoplasmic Nrf2 and enhanced nuclear translocation of Nrf2, which, in turn, upregulated antioxidant and/or phase II enzymes. These results indicate that the protective effects of DADS against CCl4 -induced hepatotoxicity possibly involve mechanisms related to its ability to induce antioxidant or detoxifying enzymes by activating Nrf2 and block metabolic activation of CCl4 by suppressing CYP2E1.
Insights
Diallyl disulfide (DADS) protects against liver injury from carbon tetrachloride (CCl4) by reducing toxic activation and boosting antioxidant defenses. DADS enhances Nrf2 activity and suppresses CYP2E1, mitigating hepatotoxicity.
Area of Science:
- Hepatology
- Toxicology
- Biochemistry
Background:
- Carbon tetrachloride (CCl4) is a potent hepatotoxin.
- CCl4-induced liver injury involves metabolic activation by cytochrome P450 2E1 (CYP2E1).
- Nuclear factor E2-related factor 2 (Nrf2) plays a crucial role in cellular defense against oxidative stress.
Purpose of the Study:
- To investigate the protective effects of diallyl disulfide (DADS) against CCl4-induced hepatotoxicity in rats.
- To elucidate the molecular mechanisms underlying DADS-induced protection.
Main Methods:
- Rats were pretreated with DADS (50 and 100 mg/kg/day) for 5 days before CCl4 administration.
- Serum enzyme activities (AST, ALT) and liver histopathology were assessed.
- Protein levels of CYP2E1 and Nrf2, and activity of antioxidant/phase II enzymes were analyzed.
Main Results:
- DADS pretreatment significantly reduced CCl4-induced elevations in AST and ALT levels.
- Histopathological examination revealed that DADS reversed CCl4-induced liver damage.
- DADS suppressed CYP2E1 protein levels and enhanced Nrf2 nuclear translocation, upregulating antioxidant and phase II enzymes.
Conclusions:
- Diallyl disulfide (DADS) exhibits significant hepatoprotective effects against CCl4-induced liver injury.
- Protection is mediated by suppressing CCl4 bioactivation via CYP2E1 inhibition.
- DADS activates the Nrf2 pathway, enhancing cellular antioxidant and detoxification capacities.
