Chemopreventive activity of glycyrrhizin on lead acetate mediated hepatic oxidative stress and its hyperproliferative activity in Wistar rats

Abstract

Lead is a pervasive environmental pollutant with no beneficial biological role and its toxicity continues to be a major health problem due to its interference with natural environment. In the present study we have evaluated the chemopreventive effect of glycyrrhizin on lead acetate mediated hepatic oxidative stress, toxicity and tumor promotion related alterations in rats. Lead acetate (100 mg/kg bwt., i.p.) enhanced lipid peroxidation with concomitant reduction in glutathione, glutathione reductase, glutathione-S-transferase and glutathione peroxidase activities. There was an increase in the levels of transaminase enzymes and LDH. Lead acetate treatment also enhanced ornithine decarboxylase (ODC) activity and [³H] thymidine incorporation into hepatic DNA. Pretreatment of rats orally with glycyrrhizin (150 and 300 mg/kg bwt., orally) resulted in a significant decrease in hepatic microsomal lipid peroxidation (P < 0.001) and increase in the level of GSH content (P < 0.001) and its dependent enzyme. There was significant reduction in the levels of SGPT, SGOT and LDH (P < 0.001). A significant inhibition in ODC activity and DNA synthesis (P < 0.001) was also observed. On the basis of the above results it can be hypothesized that glycyrrhizin is a potent chemopreventive compound against lead acetate mediated hepatic oxidative stress, toxicity and tumor promotion related responses in rats.

Introduction

Humans are exposed to various hazardous substances. Lead is one of the common environmental and industrial pollutants that has been found in the environment and the biological system. The persistence of lead in the animals and humans is now associated with health risk [1]. Lead has been found to produce wide range of biochemical and physiological dysfunctions in humans and laboratory animals [2]. The major source of lead is from industries where lead and lead based components are used, such as lead acid battery manufacturing, cable and wire products industries, rubber and plastic industries, soldering activities, in-foundry work such as casting, forging and grinding activities [3]. Pregnant ladies, infants and young children are mostly affected by lead exposure [4]. A pregnant lady can transfer her body burden of lead to the growing foetus as there is no placental barrier for a heavy metal like lead [5]. Most of the environmental exposure occurs through inhaling air containing lead dust, drinking water supplied through leaded pipelines and consuming processed, preserved and stored food [6]. Studies suggest that one of the important mechanisms associated with toxic effects of lead is oxidative stress caused by disrupted prooxidant/antioxidant balance in animals including humans. Reduced glutathione (GSH) levels and glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities in tissues or in blood are most commonly used to evaluate lead induced oxidative damage. The oxidative stress has also been implicated to contribute to lead associated tissue injury in the liver, kidneys, brain and other organs [7], [8]. Lead has been shown to increase hydrogen peroxide production in cells [9]. Another mechanism of free radical generation and adduct formation may involve aminolevulinic acid (ALA), the heme precursor whose levels are elevated by lead exposure through feedback inhibition of the enzyme ALA synthase [10]. ALA can generate free radicals and has been shown to cause oxidative damage to DNA in Chinese hamster ovary cells in vitro through the formation of 8-OHdG adducts [11]. The oxidative damage to DNA in human lead toxicity has been observed by a recent study of 7,8-dihydro-9-oxoguanine adducts in lymphocytes collected from persons exposed environmentally to metals, including lead, chromium, cadmium and nickel. Lead at high doses can induce proliferation, there is some evidence that oxygen radicals, produced by lead (especially in the presence of hydrogen peroxide) may induce DNA adducts [12]. Reactive oxygen species are important cytotoxic and signalling mediators in the pathophysiology of inflammatory liver diseases [13]. Recent studies indicate that compounds with antioxidant or anti-inflammatory properties can inhibit tumor initiation, promotion and progression in experimental models [14]. The antioxidant system may be composed of several endogenous and/or dietary antioxidant compounds and enzymes that interact with and inactivate ROS [15].

Natural components from numerous plants are used to halt or retard the carcinogenic process. Glycyrrhizin (Fig. 1) is the major biologically active component of liquorice. Glycyrrhizin is the calcium and potassium salt of glycyrrhizinic acid and upon hydrolysis, the glycoside loses its sweet taste and is converted to the aglycone glycyrrhetinic acid plus two molecules of glucuronic acid. Glycyrrhetinic acid has been shown to inhibit the activity of tumor promoter in mouse skin [16].

Glycyrrhizin exhibits a number of pharmacological effects, including anti-inflammation, anti-ulcer, anti-allergy, anti-carcinogenesis and immunomodulation [17], [18], [19], [20]. It is also used as a potential therapeutic agent for several viral diseases, including chronic hepatitis, acquired immunodeficiency syndrome and herpes infection [21].

The present study is designed to evaluate the anti-oxidative and anti-proliferative activity of glycyrrhizin against lead acetate induced early biomarkers of hepatic tumor promotion in animal model.