title: Protective role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in cisplatin-induced nephrotoxicity.
abstract: Although cisplatin is widely used as an anti-cancer agent, its use is significantly limited because of its tendency to induce nephrotoxicity through poorly understood mechanisms. NAD(P)H:quinone oxidoreductase 1 (NQO1) is well known to regulate ROS generation. The purpose of this study was to investigate whether NQO1 modulates cisplatin-induced renal failure associated with NADPH oxidase (NOX)-derived ROS production in an animal model. NQO1-/- mice were treated with cisplatin (18 mg/kg) and renal function, oxidative stress, and tubular apoptosis were assessed. NQO1-/- mice showed increased blood urea nitrogen and creatinine levels, tubular damage, oxidative stress, and apoptosis. In accordance with these results, the cellular NADPH/NADP ratio and NOX activity were markedly increased in the kidneys of NQO1-/- mice compared to NQO1+/+ mice. In addition, activation of NQO1 by βL treatment significantly improved renal dysfunction and reduced tubular cell damage, oxidative stress, and apoptosis. This study demonstrates that NQO1 protects cells against renal failure induced by cisplatin, and that this effect is mediated by decreased NOX activity via cellular NADPH/NADP modulation. These results provide convincing evidence that NQO1 might be beneficial for ameliorating renal failure induced by cisplatin.
authors.affiliation: Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology-KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Jung-Ran
authors.initials: JR
authors.lastname: Noh
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Jung
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C014638:beta-lapachone; D019255:NADPH Oxidases; D016660:NAD(P)H Dehydrogenase (Quinone); D002945:Cisplatin
keywords: Cisplatin; NADPH oxidase; NQO1; β-lapachone