Elsevier

Life Sciences

Volume 78, Issue 7, 11 January 2006, Pages 713-718
Life Sciences

Protective effect of ursolic acid on ethanol-mediated experimental liver damage in rats

https://doi.org/10.1016/j.lfs.2005.05.060Get rights and content

Abstract

Ursolic acid is a triterpenoid that exists in nature and is the major component of some traditional medicinal herbs. In this study, ursolic acid has been evaluated for its hepatoprotective effect against chronic ethanol-mediated toxicity in rats. Ethanol administration (7.9 g/kg/day) for 60 days resulted in increased oxidative stress, decreased antioxidant defense and liver injury. It also negatively affected the serum total protein, albumin and A/G ratio. Subsequent to the experimental induction of toxicity (i.e. after the initial period of 30 days) ursolic acid treatment performed by coadministering ursolic acid (10, 20 and 40 mg/kg body weight) for 30 days along with the daily dose of ethanol. While this treatment causing a significant improvement in body weight, food intake and serum protein levels, it decreases serum aminotransferase activities (aspartate aminotransferase and alanine aminotransferase) and total bilirubin levels. Ursolic acid improved the antioxidant status of alcoholic rats, which is evaluated by the decreased levels of lipid peroxidation markers in plasma (thiobarbituric acid reactive substances and lipid hydroperoxides) and increased levels of circulatory antioxidants such as reduced glutathione, ascorbic acid and α-tocopherol. Histopathological observations were also in correlation with the biochemical parameters. The activity of ursolic acid (20 mg/kg) compares well with silymarin, a known hepatoprotective drug, and seems to be better in certain parameters. The protective effect of ursolic acid is probably related to its antioxidant activities.

Introduction

Alcoholic liver disease remains one of the most common causes of chronic liver disease in the world (Diehl, 2002). Oxidative stress is known to play an important role in the pathogenesis of ethanol-induced liver injury (Lindros, 1995, Zima et al., 2001). Ethanol administration can elicit disturbances in the delicate balance between the pro- and antioxidant system of the organism, therefore leading to oxidative stress. Increased generation of oxygen- and ethanol-derived free radicals has been observed at the microsomal level (particularly at the ethanol-inducible cytochrome P450 isoform), the cytosolic xanthine and/or aldehyde oxidase, as well as through the mitochondrial respiratory chain (Nordmann et al., 1992). Polyunsaturated fatty acids are probably the most susceptible target to free radical attack. The reaction of free radicals with the membrane lipid components leads to lipid peroxidation. This process can eventually cause increased membrane permeability and cell death (Rakonczay et al., 2003).

Although important progress has been made in understanding the pathogenesis of alcoholic liver disease, current therapies for this disease are not effective. A phytotherapeutic approach to modern drug development can provide many invaluable drugs from traditional medicinal plants. Ursolic acid, a pentacyclic triterpenoid, exists widely in natural plants in the form of free acid or aglycones for triterpenoid saponins (Price et al., 1987, Mahato et al., 1988). It is of interest to scientists because of its biological activities and easy availability. It has antifungal, antiinflammatory, anticarcinogenic, antiulceric, antihyperlipidemic and antihyperglycemic activities (Liu, 1995). The antioxidant effect of ursolic acid has been well evaluated by various researchers (Kim et al., 1996, Martin-Aragon et al., 2001). It was identified as an active hepatoprotective component in the preparation of Sambucus chinesis Lindl. (Ma et al., 1986), Solanum incanum L. (Lin et al., 1988), Tripterospermum taiwanense (Gan and Lin, 1988) and Eucalyptus hybrid (Shukla et al., 1992). Ursolic acid found in herbal medicines is surprisingly similar in chemical structure to ursodeoxycholic acid (Kitani et al., 1999), a hepatoprotective found in a Chinese medicine prepared from black bear bile (Yutan) (Kitani, 1990) (Fig. 1). Although the protective effect of ursolic acid against ethanol was already evaluated in isolated rat hepatocytes (an in vitro hepatic model) (Saraswat et al., 2000), no sufficient work has been done to study its antioxidant and hepatoprotective effects on ethanol-mediated toxicity in animal model. The purpose of the present study was to evaluate the impact of ursolic acid on ethanol-mediated oxidative stress and hepatotoxicity in albino Wistar rats.

Section snippets

Materials

Ursolic acid was supplied by Sami Labs Limited, Bangalore, India. Ethanol was purchased from E. Merck, Darmstadt, Germany. All other chemicals were of analytical grade and the organic solvents were distilled before use.

Animals

Adult male albino rats of Wistar strain, bred and reared in our animal house, were used for the experiment. Weight matched animals (140–160 g) were selected and housed in plastic cages under controlled conditions of 12-h light/12-h dark cycle, 50% humidity and 25 ± 3 °C. They all

Biochemical changes

Table 1 shows the average weight gain and cumulative food intake of control and experimental rats during the experimental period. These were reduced in alcohol-administered rats as compared with that of control animals. Ursolic acid coadministered rats showed significant weight gain and increased food intake as compared to untreated alcoholic rats.

In Table 2, it can be seen that administration of ethanol produced severe liver damage as indicated by marked increase in AST and ALT activities, and

Discussion

Increasing evidences support the hypothesis that ethanol-induced tissue damage may be a consequence of oxidative stress and nutritional deficiencies (Thomson et al., 1970). Our studies are in agreement with this hypothesis, showing decreased food intake and increased oxidative stress in ethanol-administered rats. Alcohol is rich in calories (7.1 kcal/g) and devoid of nutrients. Thus, isocaloric substitution of carbohydrates by ethanol resulted in a decreased weight gain. On the other hand,

Acknowledgements

The financial support from the Indian Council of Medical Research, New Delhi is gratefully acknowledged. We are also thankful to Sami Labs Limited, Bangalore, India (The Research and Manufacturing Arm of Sabinsa Corporation) for their generous gift of ursolic acid.

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