title: Cisplatin-mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels.
abstract: Cisplatin accumulates in mitochondria, which are a major target for this drug in cancer cells. Thus alterations in mitochondrial function have been implicated in cancer cell resistance to chemotherapeutic agents. Moreover, cisplatin toxic side effects seem to be associated with mitochondrial injury in vivo and in vitro. In order to clarify the potential effect of cisplatin in mtDNA (mitochondrial DNA) maintenance and expression, we have analysed rat liver mtDNA and mtRNA (mitochondrial RNA) synthesis as well as their stability under the influence of in vivo treatment or in vitro exposure to cisplatin. We show that cisplatin causes a direct and significant impairment of mtDNA and mtRNA synthesis and decreases steady-state levels of mtRNAs in isolated mitochondria. Furthermore, in vivo treatment of the animals with cisplatin exerts a protective effect from the impairment of mtRNA metabolism caused by in vitro exposure to the drug, by means of increased mitochondrial GSH levels after in vivo cisplatin treatment.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet 177, Zaragoza 50013, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Garrido
authors.forename: Acisclo
authors.initials: A
authors.lastname: Pérez-Martos
authors.forename: Mercedes
authors.initials: M
authors.lastname: Faro
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lou-Bonafonte
authors.forename: Patricio
authors.initials: P
authors.lastname: Fernández-Silva
authors.forename: Manuel José
authors.initials: MJ
authors.lastname: López-Pérez
authors.forename: Julio
authors.initials: J
authors.lastname: Montoya
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Enríquez
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077278:RNA, Mitochondrial; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012313:RNA; D005978:Glutathione; D002945:Cisplatin