Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver.
Cisplatin is a potent and widely used chemotherapeutic agent. Nephrotoxicity induced by this drug has been well documented. However, very little information is available on cisplatin-induced hepatotoxicity and its underlying mechanism remains unclear. High doses of cisplatin have been known to produce hepatotoxicity. Additionally, elevated expression of CYP 2E1 has been associated with enhanced cisplatin-induced hepatotoxicity. Several studies suggest that cisplatin toxicity occurs by the increased generation of reactive oxygen species (ROS) in mitochondria. Therefore, the present study examined, in vivo, the cisplatin-induced effects on hepatic mitochondrial structure and function as well as the occurrence of hepatocellular death by apoptosis. Adult male Wistar rats (200-220 g) were divided into two groups (n=8) treated as follows: (1) control group (saline solution, 1 ml 100 g(-1) body weight, i.p.) and (2) cisplatin group (10 mg kg(-1) body weight, i.p.). The animals were killed 72 h after the treatment. Hepatotoxicity was evidenced in the cisplatin group by the increased serum levels of alanine (ALT) and aspartate (AST) aminotransferases. The mechanism of cisplatin-induced hepatotoxicity was found to involve membrane rigidification; decreased GSH/GSSG ratio, ATP, GSH and NADPH levels; lipid peroxidation; oxidative damage of cardiolipin and protein sulfhydryl groups. Moreover, cell death by apoptosis was also demonstrated and the findings strongly suggest the participation of the mitochondrial signaling pathway in this process. Therefore, the results show the key role of mitochondria in the hepatotoxicity induced by cisplatin and delineate several mitochondrial processes that could be targeted in future cytoprotective therapy approaches.
Martins
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NM
Departmento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brasil.
Santos
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Curti
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C
Bianchi
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ML
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AC
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D002308:Cardiolipins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D002308:Cardiolipins; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D002945:Cisplatin