Dimethylthiourea protects against mitochondrial oxidative damage induced by cisplatin in liver of rats.
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.
dos Santos
Neife Aparecida Guinaim
NA
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil. neife@fcfrp.usp.br
Martins
Nádia Maria
NM
Curti
Carlos
C
Pires Bianchi
Maria de Lourdes
Mde L
dos Santos
Antonio Cardozo
AC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D002945:Cisplatin / Q000633:toxicity*; D019610:Cytoprotection / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000255:Adenosine Triphosphate; C038983:1,3-dimethylthiourea; D013890:Thiourea; D002945:Cisplatin