The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats.
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 100 mg/kg/day was administered orally once daily for 5 days, 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.
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
In-Chul
IC
Lee
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Sung-Hwan
SH
Kim
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Hyung-Seon
HS
Baek
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Changjong
C
Moon
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Seong-Soo
SS
Kang
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Sung-Ho
SH
Kim
College of Veterinary Medicine, Chungbuk National University, Cheongju 361-763, Republic of Korea.
Yun-Bae
YB
Kim
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea. Electronic address: dvmmk79@gmail.com.
In-Sik
IS
Shin
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: toxkim@jnu.ac.kr.
Jong-Choon
JC
Kim
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D017931:DNA Primers; D004220:Disulfides / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
D000498:Allyl Compounds; D017931:DNA Primers; D004220:Disulfides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; C028009:diallyl disulfide; D002251:Carbon Tetrachloride; D053148:Caspase 3; D005978:Glutathione
ALT; ANOVA; ARE; AST; Bax; Bcl-2-associated X; CCl(4); CYPs; Carbon tetrachloride; Cox-2; DADS; Diallyl disulfide; GAPDH; GPx; GR; GSH; GSTα; H&E; HO-1; Hepatotoxicity; I kappaB alpha; IKK; IL-1β; IL-6; IκB kinase; IκBα; Keap1; Kelch like-ECH-associated protein 1; MDA; NAD(P)H quinine oxidoreductase; NF-κB; NQO1; Nrf2; Nuclear factor E2-related factor 2; Nuclear factor kappaB; ROS; RT-PCR; SOD; TNF-α; TUNEL; Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; alanine aminotransferase; analysis of variance; antioxidant response element; aspartate aminotransferase; carbon tetrachloride; cyclooxygenase-2; cytochrome P450 isoenzymes; diallyl disulfide; glutathione S-transferase alpha; glutathione peroxidase; glutathione reductase; glyceraldehydes-3-phosphate dehydrogenase; hematoxylin and eosin; heme oxygenase-1; iNOS; inducible nitric oxide synthase; interleukin-1β; interleukin-6; malondialdehyde; nuclear factor E2-related factor 2; nuclear factor-kappaB; p-IκBα; phosphor-I kappa B alpha; reactive oxygen species; real-time polymerase chain reaction; reduced glutathione; superoxide dismutase; tumor necrosis factor-alpha