The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats

• Published in: Food and chemical toxicology Vol. 63; pp. 174 - 185
• Main Authors: Lee, In-Chul, Kim, Sung-Hwan, Baek, Hyung-Seon, Moon, Changjong, Kang, Seong-Soo, Kim, Sung-Ho, Kim, Yun-Bae, Shin, In-Sik, Kim, Jong-Choon
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.01.2014; Elsevier
• Subjects: Allyl Compounds - pharmacology; Animals; antioxidant activity; antioxidants; apoptosis; Apoptosis - drug effects; Base Sequence; Biological and medical sciences; blood serum; Blotting, Western; Carbon tetrachloride; Carbon Tetrachloride - toxicity; Caspase 3 - metabolism; caspase-3; cytochrome c; cytokines; Diallyl disulfide; Disulfides - pharmacology; DNA Primers; enzyme activity; Glutathione - metabolism; Hepatotoxicity; histopathology; IKappaB kinase; inflammation; Inflammation - prevention & control; liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Medical sciences; NF-E2-Related Factor 2 - physiology; NF-kappa B - metabolism; Nuclear factor E2-related factor 2; Nuclear factor kappaB; oral administration; Oxidative Stress - drug effects; Phosphorylation; protective effect; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Toxicology; transcription factor NF-kappa B; CYPs; Carbon tetrachloride; ALT; HO-1; MDA; NF-κB; DADS; TUNEL; ANOVA; Nrf2; RT-PCR; iNOS; GSH; Hepatotoxicity; NQO1; AST; Diallyl disulfide; H&E; GSTα; IKK; SOD; GR; IL-1β; GPx; IL-6; IκBα; ARE; TNF-α; Cox-2; p-IκBα; CCl4; ROS; Bax; Keap1; GAPDH; Nuclear factor E2-related factor 2; Nuclear factor kappaB; Oxidative stress; Rat; Toxicity; Liver; Rodentia; Hepatic disease; Inflammation; Organic sulfide; Prevention; Vertebrata; Mammalia; Carbon disulfide; Animal; Digestive diseases; Garlic; Transcription factor; Mechanism of action; cyclooxygenase-2; cytochrome P450 isoenzymes; alanine aminotransferase; CCl; interleukin-6; IκB kinase; tumor necrosis factor-alpha; glutathione reductase; malondialdehyde; I kappaB alpha; heme oxygenase-1; superoxide dismutase; glutathione peroxidase; NAD(P)H quinine oxidoreductase; Bcl-2-associated X; phosphor-I kappa B alpha; inducible nitric oxide synthase; interleukin-1β; analysis of variance; reduced glutathione; reactive oxygen species; antioxidant response element; hematoxylin and eosin; glyceraldehydes-3-phosphate dehydrogenase; glutathione S-transferase alpha; real-time polymerase chain reaction; Kelch like-ECH-associated protein 1; Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; aspartate aminotransferase; nuclear factor-kappaB
• ISSN: 0278-6915; 1873-6351; 1873-6351
• DOI: 10.1016/j.fct.2013.11.006

•Diallyl disulfide showed protective effects against carbon tetrachloride-induced hepatotoxicity in rats.•It enhanced phase II detoxifying or antioxidant enzyme activities by activating nuclear factor E2-related factor 2.•It reduced hepatocellular apoptotic changes caused by carbon tetrachloride through mitochondrial pathway.•It suppressed inflammatory response by inhibiting nuclear factor kappaB activation and I kappaB phosphorylation. This study investigated the potential effect of diallyl disulfide (DADS) against carbon tetrachloride (CCl4)-induced oxidative hepatic damage and inflammatory response in rat liver. DADS at doses of 50 and 100mg/kg/day was administered orally once daily for 5days, prior to CCl4 administration. Pretreatment with DADS attenuated CCl4-induced elevated serum transaminase activities and histopathological alterations in liver. It prevented the hepatocellular apoptotic changes with induction of Bcl-2-associated X (Bax), cytochrome c, and caspase-3 caused by CCl4. An increase in the nuclear translocation of nuclear factor-kappaB (NF-κB) and phosphorylation of I kappaB alpha (IκBα) was observed in the livers of CCl4-treated rats that coincided with induction of inflammatory mediators or cytokines. In contrast, DADS inhibited NF-κB translocation and IκBα phosphorylation, and that subsequently decreased inflammatory mediators. Furthermore, DADS prevented CCl4-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. Taken together, these results demonstrate that DADS increases the expression of phase II/antioxidant enzymes and simultaneously decreases the expression of inflammatory mediators in CCl4-induced liver injury. These findings indicate that DADS induces antioxidant defense mechanism by activating Nrf2 pathway and reduces inflammatory response by inhibiting NF-κB activation.