Combined efficacies of lipoic acid and 2,3-dimercaptosuccinic acid against lead-induced lipid peroxidation in rat liver R. Sivaprasad, M. Nagaraj, P. Varalakshmi* Department of Medical Biochemistry, Dr. A. L. Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras (Taramani), Chennai 600 113, India Abstract Oxidative stress with subsequent lipid peroxidation has been postulated as one mechanism for lead toxicity. Hence in assessing the protective effects of lipoic acid (LA) and meso 2,3-dimercaptosuccinic acid (DMSA) on lead toxicity, they were tested either separately or in combination for their effects on selected indices of hepatic oxidative stress. Elevated levels of lipid peroxides were accompanied by altered antioxidant defense systems. Lead acetate (Pb - 0.2%) was administered in drinking water for five weeks to induce toxicity. LA (25 mg kg -1 body wt. day -1 i.p) and DMSA (20 mg kg -1 body wt. day -1 i.p) were administered individually and also in combination during the sixth week. Lead damage to the liver was evident in the decreases in hepatic enzymes alanine transaminase (-38%), aspartate transaminase (-42%) and alkaline phosphatase (-43%); increases in lipid peroxidation (+38%); decreases in the antioxidant enzymes catalase (-45%), superoxide dismutase (-40%), glutathione peroxidase (-46%) and decreases in glutathione (-43%) and decreases in glutathione metabolizing enzymes, glutathione reductase (-59%), glucose-6-phosphate dehydrogenase (-27%) and glutathione-S-trans- ferase (-42%). In combination LA and DMSA completely ameliorated the lead induced oxidative damage. Either compound alone was however only partially protective against lead damage. © 2004 Elsevier Inc. All rights reserved. Keywords: Lead acetate; DL--lipoic acid; Meso 2,3-dimercaptosuccinic acid; Lipid peroxidation; Antioxidants 1. Introduction Lead is a non-essential toxic heavy metal widely distrib- uted in the environment and chronic exposure to low levels of lead has been a matter of public health concern in many countries. Lead induces a broad range of physiological, biochemical and behavioral dysfunctions. Many studies have explored the mechanisms and symptoms of this tox- icity through the years but recent studies have reported lead as a potential agent for inducing oxidative stress by the production of reactive oxygen species (ROS) [1]. Approximately 90% of the total body lead is contained within bones [2]. Blood accounts for 4% and the remaining lead resides mainly in the liver and the kidneys [3]. The liver and the kidneys are also known to play a major role in the elimination of lead [4] and hence account for the toxic actions [5]. Lead is known to produce oxidative damage in the liver tissues by enhancing peroxidation of membrane lipids [6], a deleterious process solely carried out by free radicals [7]. Many studies have investigated possible relationship be- tween lipid peroxidation (LPO) and cellular damage in hepatic tissues under various pathological conditions [8]. Lewis and Wills [9], have suggested that peroxide formation may lead to oxidative destruction of thiol groups of amino acids and proteins. Reports on lead-induced oxidative stress dates back to 1965 [10]. Lead can cause derangement of several hepatic biochemical pathways and energy metabo- lism [11]. In particular lead causes transient, but marked hypercalaemia, which may contribute to hepatotoxicity [12]. Cell membranes are targets for oxidative damage pro- duced by xenobiotics including heavy metals [7]. Peroxida- tive decomposition of membrane lipids is catastrophic for living system. Antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) scavenge free radicals and lipid peroxides and detox- ify them [13]. Previous reports by Dwivedi et al. [13] and * Corresponding author. Tel.: +91-44-24925548; fax: +91-44- 24926709. E-mail address: drvlakshmi@yahoo.com (P. Varalakshmi). Journal of Nutritional Biochemistry 15 (2004) 18-23 0955-2863/04/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.jnutbio.2003.09.001