cell biochemistry and function Cell Biochem Funct 2004; 22: 265–271. Published online 22 January 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1027/cbf.1099 Antioxidant-associated chemoprevention by sodium selenite in N-nitrosodiethylamine-induced and phenobarbital-promoted hepatocarcinogenesis in rats C. Thirunavukkarasu* y , E. Babu, A. S. Ebrahim, N. Chandramohan and D. Sakthisekaran Department of Medical Biochemistry, Dr ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai-600 113, India The anticarcinogenic/antioxidant potential of sodium selenite (Se), a micronutrient, was evaluated on liver tumourigenesis induced by N-nitrosodiethylamine (DEN) and promoted by phenobarbital (PB; 0.05% in diet). Male, albino rats of the Wistar strain were exposed intravenously to a single dose of DEN (200 mg kg 1 body weight). Se (4 ppm in drinking water) was supplemented before initiation, or during initiation and/or during the promotion period of carcinogenesis. At the end of 16 weeks (after DEN administration) nodular incidence, the total number of nodules and non-enzymic antioxidants such as vitamin E, vitamin C, total thiol, protein thiol and non-protein thiol contents were measured in hepatoma, surrounding tissue and kidney tissue of control and experimental groups. In hepatoma-bearing animals the above biochemical changes were decreased when compared with normal control animals. On Se treatment throughout the study, (20 weeks) the above bio- chemical changes reverted to normal levels. Pre- and post-treatment with Se also shows a tendency to reverse the above changes. The results indicate that prior application of Se significantly reverses the adverse changes produced during the tumourigenesis. Furthermore, prior applications of Se significantly reduced the cumulative number of tumours per tumour-bearing animals. The present study reveals the antitumour potential of Se against DEN-induced liver carcinogenesis. Copyright # 2004 John Wiley & Sons, Ltd. key words — selenium; antioxidant defence; hepatocarcinogenesis; N-nitrosodiethylamine abbreviations — Se, sodium selenite; DEN, N-nitorsodiethylamine INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most common tumours and causes the death of 1 300 000 people worldwide every year. 1,2 Morbidity and mor- tality in HCC are primarily the result of aggressive local spread rather than the occurrence of distant metastasis. No effective therapy can be offered to patients with unresectable HCC since conventional chemotherapy or radiotherapy is ineffective in this form of malignancy. 3,4,5 Thus new therapies are needed. Se is a dietary essential trace element, which is found to possess important physiological functions. 6 Epidemiological investigations indicate an inverse correlation of selenium intake level with cancer risk in humans, and experimental studies with animal models also strongly support the chemopreventive effectiveness of Se compounds. 7–12 Based on experi- mental studies, the anticarcinogenic activity of Se mainly depends on two important factors: the dosage and chemical form. 13,14 Oxidative stress is implicated in the cytotoxicity of selenite and in inhibition of can- cer cell growth. 15 However, in vivo studies by Lanfear et al. 16 and also by us 12,17,18 showed that the antican- cer effect of Se may also depend on the molecules associated with the trace element. Received 5 December 2002 Revised 24 June 2003 Copyright # 2004 John Wiley & Sons, Ltd. Accepted 8 July 2003 * Correspondence to: Dr C. Thirunavukkarasu, Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, W-1518 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Tel: (412) 624 0288. Fax: (412) 624 6666. E-mail: tchinnasamy@hotmail.com y Present address: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, W-1518, BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA.