Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-a and NF-kB activation Mir Tahir, Muneeb U. Rehman, Abdul Lateef, Rehan Khan, Abdul Quaiyoom Khan, Wajhul Qamar, Farrah Ali, Oday O’Hamiza, Sarwat Sultana * Molecular Carcinogenesis and Chemoprevention Division, Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India article info Article history: Received 11 April 2012 Received in revised form 17 December 2012 Accepted 20 December 2012 Keywords: Ethanol Cytochrome P450 2E1 Alcohol dehydrogenase Tumor necrosis factor-alpha Cyclooxygenase-2 abstract The present investigation was designed to evaluate the efficacy of diosmin against ethanol-induced hepatotoxicity in rats by modulating various mechanisms including ethanol metabolizing enzymes, generation of free radicals, imbalance in oxidanteantioxidant status, oxidative damage to membrane lipids, activation of transcription factors and elevation in inflammatory markers involved in ethanol- induced hepatic damage. Diosmin is a flavone glycoside, having anti-inflammatory and anti-cancer properties. Thirty female Wistar rats segregated in five groups, each with six animals. Group I as control followed by Group II, III and IV were treated with ethanol for 28 days. While groups III and IV were administered with diosmin at 10 mg/kg b wt (D1) and 20 mg/kg b wt (D2) respectively prior to ethanol administration. Group V was given only higher dose of diosmin. In ethanol-treated group, ethanol metabolizing enzymes viz., CYP 450 2E1 and alcohol dehydrogenase (ADH) significantly increased by 77.82% and 32.32% in liver tissues respectively as compared with control group and this enhancement is significantly normalized with diosmin administration. Diosmin administration (D1 & D2) significantly (p < 0.001) attenuates oxidative stress markers i.e., LPO, GSH, GPx, GR and XO by 90.77 & 137.55%, 17.18 & 25%, 37.3 & 49.86%, 21.63 & 44.9% and 56.14 &77.19% respectively. Serum ALT, AST and LDH significantly increased by 102.03, 116.91 and 45.20% in ethanol-treated group as compared with control group. Group III and IV animals showed significant reduction in the serum toxicity markers. Diosmin further alleviated ethanol-induced NF-kB activation, enhanced expression of TNF-a, COX-2 and iNOS. Findings from the present study permit us to conclude that diosmin alleviates alcoholic liver injury via modulating ethanol metabolizing pathway, inhibition of oxidative stress markers and suppression of inflammatory markers. This may represent a novel protective strategy against ethanol-induced liver diseases. Ó 2013 Elsevier Inc. All rights reserved. Introduction Alcoholic liver diseases are the most challenging current health problems worldwide. Over the period of time, alcohol (ethanol) has evolved as one of the socially accepted addictive drugs worldwide (Guo & Ren, 2010). Ethanol consumption can lead to various alco- holic liver diseases ranging from steatohepatitis, cirrhosis (Lucey & Weinrieb, 2009), heart disease (George & Figueredo, 2010), Alz- heimer’s disease (Marinho, Laks, Engelhardt, & Conn, 2006), stroke (Ohkubo, Metoki, & Imai, 2009), liver disease (Cederbaum, Lu, & Wu, 2009), respiratory disease (Morris, 1990), diabetes mellitus (Baliunas et al., 2009), bone disease (Chen, Cui, Liao, & Huang, 2009) to cancer (Seitz & Becker, 2007), which may develop following chronic alcohol ingestion and contribute to the alcoholism-related high morbidity and mortality. Ethanol as such is a mild toxicant and its toxicity primarily depends upon its metabolism. Liver is the primary target for ethanol toxicity as it is the main organ for ethanol metabolism (Lieber, 1988). Besides liver, other organs (Kidney, brain, and lungs) may also contribute to ethanol metabolism (Guidot & Roman, 2002). In liver, ethanol is metabolized to highly toxic metabolite e acetaldehyde that interacts with the cellular macromolecules (lipids and proteins) and leads to the damage of membrane lipids besides altering the enzyme activities (Niemelä, 1999). Three main enzyme systems are involved in ethanol metabolism (Salaspuro, 1999): alcohol dehydrogenase (ADH), Cytochrome P450 2E1 (CYP * Corresponding author. Department of Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India. Tel.: þ91 11 26054685x5565/5566/26089688; fax: þ91 11 26059663. E-mail address: sarwat786@rediffmail.com (S. Sultana). Contents lists available at SciVerse ScienceDirect Alcohol journal homepage: http://www.alcoholjournal.org/ 0741-8329/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.alcohol.2012.12.010 Alcohol 47 (2013) 131e139