Arch Pharm Res Vol 33, No 6, 925-932, 2010 DOI 10.1007/s12272-010-0616-4 925 Resveratrol Inhibits Dimethylnitrosamine-Induced Hepatic Fibrosis in Rats Eun-Sil Lee 1 , Mi-Ok Shin 1,2 , Sik Yoon 3 , and Jeon-Ok Moon 1 1 College of Pharmacy, Pusan National University, Busan 609-735, Korea, 2 Department of Food and Nutrition, Silla Uni- versity, Busan 617-736, Korea, and 3 Department of Anatomy, College of Medicine, Pusan National University, Busan 602-739, Korea (Received December 17, 2009/Revised January 29, 2010/Accepted March 22, 2010) Resveratrol, a phytoalexin found in grapes and red wines, has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of res- veratrol on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Oral administra- tion of resveratrol (20 mg/kg daily for 4 weeks) remarkably prevented the DMN-induced loss in body and liver weight, and inhibited the elevation of serum alanine transaminase, aspar- tate transaminase, alkaline phosphatase and bilirubin levels. Resveratrol also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialde- hyde due to its antioxidant effect. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the resveratrol treated rats, the result of which was consistent with the reduction in type I collagen mRNA expression and the histological analysis of liver tissue stained with Sirius red. The reduction in hepatic stellate cell activation, as assessed by α- smooth muscle actin staining, and the reduction in transforming growth factor-β1 mRNA expression were associated with resveratrol treatment. In conclusion, resveratrol exhibited in vivo hepatoprotective and antifibrogenic effects against DMN-induced liver injury, suggesting that resveratrol may be useful in the prevention of the development of hepatic fibrosis. Key words: Resveratrol, Hepatoprotective effect, Antifibrogenic effect, Antioxidant effect, Hepatic stellate cell, TGF-β1 INTRODUCTION Hepatic fibrosis is a wound-healing response to chronic liver injury that leads to cirrhosis and liver failure if repetitive liver damages occur. Exciting progress has been made in the understanding of the mechanisms of hepatic fibrosis, which demonstrates that the central event of liver fibrosis is the activation of stellate cells involving the transformation of quies- cent vitamin-A-rich cells into proliferative, fibrogenic and contractile myofibroblasts (Friedman, 2008a, 2008b). Therefore, targeting the stellate cells and fibrogenic mediators could be a mainstay of antifibrotic therapy (Moreira, 2007). Resveratrol (trans-3,5,4’-trihydroxystilbene) is a natural phytoalexin found in grapes and red wines, which has been reported to exhibit a wide range of pharmacological properties and is believed to play a role in the prevention of human cardiovascular disease (Athar et al., 2007). Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-κB (NF-κB) activity (Shankar et al., 2007). Because inflammatory mediators may stimulate hepatic stellate cell (HSC) activation (Wallace et al., 2008), it is conceivable that the anti-inflammatory effect of resveratrol may contribute to its antifibrotic activity in the injured liver via inhibition of HSC activation. Several in vitro studies have documented the inhibition of stellate cell activation by resveratrol using rat HSCs (Kawada et al., 1998) and cultured human liver myofibroblasts (Godichaud et al., 2000; Godichaud et al., 2006). And the hepatoprotective and Correspondence to: Jeon-Ok Moon, College of Pharmacy, Pusan National University, Busan 609-735, Korea Tel: 82-51-510-2808, Fax: 82-51-513-6754 E-mail: mjo@pusan.ac.kr