title: Protective effects of diallyl disulfide on carbon tetrachloride-induced hepatotoxicity through activation of Nrf2.
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.
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chonnam National University, Gwangju, 500-757, Republic of Korea.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Lee
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyung-Seon
authors.initials: HS
authors.lastname: Baek
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Yun-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Won-Kee
authors.initials: WK
authors.lastname: Yun
authors.forename: Hyoung-Chin
authors.initials: HC
authors.lastname: Kim
authors.forename: Jong-Choon
authors.initials: JC
authors.lastname: Kim
mesh_terms: D065767:Activation, Metabolic; D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D000498:Allyl Compounds; D000975:Antioxidants; D004220:Disulfides; D051267:NF-E2-Related Factor 2; C028009:diallyl disulfide; D019392:Cytochrome P-450 CYP2E1
keywords: carbon tetrachloride; cytochrome P450 2E1; diallyl disulfide; hepatotoxicity; nuclear factor E2-related factor 2