Cisplatin-mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels.
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.
Garrido
Nuria
N
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet 177, Zaragoza 50013, Spain.
Pérez-Martos
Acisclo
A
Faro
Mercedes
M
Lou-Bonafonte
José Manuel
JM
Fernández-Silva
Patricio
P
López-Pérez
Manuel José
MJ
Montoya
Julio
J
Enríquez
José Antonio
JA
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
D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012313:RNA; D005978:Glutathione; D002945:Cisplatin