Protective effect of sulforaphane against cisplatin-induced mitochondrial alterations and impairment in the activity of NAD(P)H: quinone oxidoreductase 1 and γ glutamyl cysteine ligase: studies in mitochondria isolated from rat kidney and in LLC-PK1 cells.
This work was designed to further study the mechanism by which sulforaphane (SFN) exerts a renoprotective effect against cisplatin (CIS)-induced damage. It was evaluated whether SFN attenuates the CIS-induced mitochondrial alterations and the impairment in the activity of the cytoprotective enzymes NAD(P)H: quinone oxidoreductase 1 (NQO1) and γ glutamyl cysteine ligase (γGCL). Studies were performed in renal epithelial LLC-PK1 cells and in isolated renal mitochondria from CIS, SFN or CIS+SFN treated rats. SFN effectively prevented the CIS-induced increase in reactive oxygen species (ROS) production and the decrease in NQO1 and γGCL activities and in glutathione (GSH) content. The protective effect of SFN on ROS production and cell viability was prevented by buthionine sulfoximine (BSO), an inhibitor of γGCL, and by dicoumarol, an inhibitor of NQO1. SFN was also able to prevent the CIS-induced mitochondrial alterations both in LLC-PK1 cells (loss of membrane potential) and in isolated mitochondria (inhibition of mitochondrial calcium uptake, release of cytochrome c, and decrease in GSH content, aconitase activity, adenosine triphosphate (ATP) content and oxygen consumption). It is concluded that the protection exerted by SFN on mitochondrial alterations and NQO1 and γGCL enzymes may be involved in the renoprotection of SFN against CIS.
Guerrero-Beltrán
Carlos Enrique
CE
Departamento de Biología, Facultad de Química, Edificio F, Lab 209, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, D.F., Mexico.
Calderón-Oliver
Mariel
M
Martínez-Abundis
Eduardo
E
Tapia
Edilia
E
Zarco-Márquez
Guillermo
G
Zazueta
Cecilia
C
Pedraza-Chaverri
José
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D017879:Isothiocyanates; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018374:LLC-PK1 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D028361:Mitochondrial Diseases / Q000517:prevention & control*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010101:Oxygen Consumption; D051381:Rats; D013454:Sulfoxides; D013552:Swine; D013861:Thiocyanates / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005721:Glutamate-Cysteine Ligase; C016766:sulforaphane; D005978:Glutathione; D002945:Cisplatin