Inhibition of Renal NQO1 Activity by Dicoumarol Suppresses Nitroreduction of Aristolochic Acid I and Attenuates its Nephrotoxicity
文献类型：期刊论文
| 作者 | Chen, Min; Gong, Likun ; Qi, Xinming; Xing, Guozhen; Luan, Yang; Wu, Yuanfeng; Xiao, Ying; Yao, Jun; Li, Yan; Xue, Xiang
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| 刊名 | TOXICOLOGICAL SCIENCES
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| 出版日期 | 2011-08 |
| 卷号 | 122期号:2页码:288-296 |
| 关键词 | aristolochic acid nephropathy NQO1 nitroreduction aristolactam I dicoumarol |
| ISSN号 | 1096-6080 |
| DOI | 10.1093/toxsci/kfr138 |
| 文献子类 | Article |
| 英文摘要 | Aristolochic acid I (AAI) is the major toxic component of aristolochic acid that causes aristolochic acid nephropathy and Balkan endemic nephropathy . Nitroreduction is an essential metabolic process for AAI rapid clearance in different species including humans. However, which enzyme participates in AAI nitroreduction in vivo and whether this metabolic process contributes to AAI nephrotoxicity are unclear. Here, we showed that NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in mouse renal tubular epithelial cells. Inhibition of NQO1 activity by dicoumarol pretreatment significantly decreased renal aristolactam I (ALI) levels, a major reductive metabolite of AAI, whereas it increased renal AAI and its major oxidative metabolite 8-hydroxy-aristolochic acid I (AAIa) levels in male C57BL/6 mice. Similar changes in renal ALI, AAI, and AAIa levels were also observed in mice pretreated with another NQO1 inhibitor, phenindione. Consistent with higher levels of renal AAI and AAIa found in dicoumarol-pretreated mice, their serum clearance was much slower compared with vehicle-pretreated mice. The survival rate of mice pretreated with dicoumarol was markedly increased when higher doses of AAI were given. Similarly, pretreatment of mice with phenindione also attenuated AAI-induced nephrotoxicity. These results indicate that NQO1 plays an important role in renal AAI nitroreduction and may thus contribute to AAI-induced nephrotoxicity. |
| WOS关键词 | CHINESE HERBS NEPHROPATHY ; BALKAN ENDEMIC NEPHROPATHY ; PROSTAGLANDIN-H SYNTHASE ; CYTOCHROMES P450 1A1/2 ; DNA ADDUCT FORMATION ; DT-DIAPHORASE ; REDUCTIVE ACTIVATION ; METABOLIC-ACTIVATION ; UROTHELIAL CANCER ; PROTECTS MICE |
| 资助项目 | National Grand Fundamental Research 973 Program of China[2006CB504700] ; National Key Technologies RD Program[2008ZX09305-007] ; National Key Technologies RD Program[2009ZX09501-033] ; National Science and Technology Major Project, China[2008ZX09305-007] ; National Science and Technology Major Project, China[2009ZX09501-033] ; National Science and Technology Major Project, China[2009ZX09301-001] |
| WOS研究方向 | Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:000293914500006 |
| 出版者 | OXFORD UNIV PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278458]  |
| 专题 | 药物安全性评价中心 药物化学研究室 |
| 通讯作者 | Chen, Min |
| 作者单位 | Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, State Key Lab New Drug Res, Shanghai Inst Mat Med,Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Min,Gong, Likun,Qi, Xinming,et al. Inhibition of Renal NQO1 Activity by Dicoumarol Suppresses Nitroreduction of Aristolochic Acid I and Attenuates its Nephrotoxicity[J]. TOXICOLOGICAL SCIENCES,2011,122(2):288-296. |
| APA | Chen, Min.,Gong, Likun.,Qi, Xinming.,Xing, Guozhen.,Luan, Yang.,...&Ren, Jin.(2011).Inhibition of Renal NQO1 Activity by Dicoumarol Suppresses Nitroreduction of Aristolochic Acid I and Attenuates its Nephrotoxicity.TOXICOLOGICAL SCIENCES,122(2),288-296. |
| MLA | Chen, Min,et al."Inhibition of Renal NQO1 Activity by Dicoumarol Suppresses Nitroreduction of Aristolochic Acid I and Attenuates its Nephrotoxicity".TOXICOLOGICAL SCIENCES 122.2(2011):288-296. |
入库方式： OAI收割
来源：上海药物研究所
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