Chemico-Biological Interactions 170 (2007) 177–186 Available online at www.sciencedirect.com Dimethylthiourea protects against mitochondrial oxidative damage induced by cisplatin in liver of rats Neife Aparecida Guinaim dos Santos a , N´ adia Maria Martins a , Carlos Curti b , Maria de Lourdes Pires Bianchi a , Antonio Cardozo dos Santos a,∗ a Departamento de An ´ alises Cl´ ınicas, Toxicol´ ogicas e Bromatol´ ogicas, Faculdade de Ciˆ encias Farmacˆ euticas de Ribeir ˜ ao Preto-USP, Avenida do Caf´ e s/n, 14040-903 Ribeir ˜ ao Preto, SP, Brazil b Departamento de F´ ısica e Qu´ ımica, Faculdade de Ciˆ encias Farmacˆ euticas de Ribeir ˜ ao Preto-USP, Avenida do Caf´ e s/n, 14040-903 Ribeir ˜ ao Preto, SP, Brazil Received 31 May 2007; received in revised form 30 July 2007; accepted 31 July 2007 Available online 6 August 2007 Abstract Cisplatin is one of the most effective chemotherapeutic agents. However, at higher doses liver injury may occur. The purpose of this study was to explore whether the hydroxyl radical scavenger dimethylthiourea (DMTU) protects against cisplatin-induced oxidative damage in vivo and to define the mitochondrial pathways involved in cytoprotection. Adult male Wistar rats (200–220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The DMTU group was given only DMTU (500 mg/kg body weight, i.p), followed by 125 mg/kg body weight, i.p. (twice a day) until sacrifice. The cisplatin group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The DMTU + cisplatin group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until sacrifice (72 h after the treatment). DMTU did not present any direct effect on mitochondria and substantially inhibited cisplatin-induced mitochondrial damage in liver, therefore preventing elevation of AST and ALT serum levels. DMTU protected against (a) decreased hepatic ATP levels; (b) lipid peroxidation; (c) cardiolipin oxidation; (d) sulfhydryl protein oxidation; (e) mitochondrial membrane rigidification; (f) GSH oxidation; (g) NADPH oxidation; (h) apoptosis. Results suggest that antioxidants, particularly hydroxyl radical scavengers, protect liver mitochondria against cisplatin-induced oxidative damage. Several mitochondrial changes were delineated and proposed as interesting targets for cytoprotective strategy. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Cisplatin; Cytoprotection; Liver; Mitochondria; ROS; DMTU ∗ Corresponding author. Tel.: +55 16 3602 4159; fax: +55 16 3602 4725. E-mail addresses: neife@fcfrp.usp.br (N.A.G. dos Santos), toxicon@fcfrp.usp.br (N.M. Martins), curti@fcfrp.usp.br (C. Curti), mdlpbian@usp.br (M.d.L. Pires Bianchi), acsantos@fcfrp.usp.br (A.C. dos Santos). 1. Introduction Cisplatin [cis-(NH 3 ) 2 PtCl 2 ] is one of the most effec- tive drugs to treat testicular, ovarian, bladder and neck cancers. It is also used in the management of endometrial cancer, non-small cell lung cancer, malignant melanoma, penile cancer and adrenocorticol carcinoma. The most common side effects of cisplatin chemotherapy are 0009-2797/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2007.07.014