Genotoxic effect and nitrative DNA damage in HepG2 cells exposed to aristolochic acid

Wu, Keya; Jiang, Liping; Cao, Jun; Yang, Guang; Chen, Geng; Zhong, Laifu

doi:10.1016/j.mrgentox.2007.03.006

Cited by 20 publications

(16 citation statements)

References 35 publications

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“…These findings were similar to those reported by Wu et al (34). They used comet and micronucleus test to identify the genotoxicity of AA and found a clear dosedependent manner (25-200 μM AA) increase in tail DNA movement and a significant increase in frequencies of micronuclei (12.5-50 μM AA) in human hepatoma HepG2 cells (34). They also found that AA at concentrations ≥50 μM caused a significant increase in NO and 8-OHdG levels and assumed that high-dose AA exerted genotoxicity probably via NO in HepG2 cells.…”

Section: ------------------------------------------------------------supporting

confidence: 93%

“…Balachandran et al (31) and Li et al (32) have used a porcine proximal tubular epithelial cell line (LLC-PK1) to study DNA damage, cell cycle perturbations, and cell apoptosis induced by AA. Human urinary tract epithelium cells (SV-HUC-1), human hepatoma HepG2 cells, and human colorectal cancer cells (HCT 116) (33)(34)(35) have also been used to study the cytotoxicity or genotoxicity of AA. Chen et al (36) have shown that more cancer-related genes were significantly altered in target (kidney) tissues than in non-target (liver) tissues in AA-treated rats, suggesting that studies on the toxic effects of AA should be conducted in renal cells.…”

Section: Introductionmentioning

confidence: 99%

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Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

Chen

Chung²,

et al. 2010

Oncol Rep

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Abstract. Aristolochic acid (AA), derived from plants of the Aristolochia genus, has been proven to be associated with aristolochic acid nephropathy (AAN) and urothelial cancer in AAN patients. In this study, we used toxicogenomic analysis to clarify the molecular mechanism of AA-induced cytotoxicity in normal human kidney proximal tubular (HK-2) cells, the target cells of AA. AA induced cytotoxic effects in a dose-dependent (10, 30, 90 μM for 24 h) and timedependent manner (30 μM for 1, 3, 6, 12 and 24 h). The cells from those experiments were then used for microarray experiments in triplicate. Among the differentially expressed genes analyzed by Limma and Ingenuity Pathway Analysis software, we found that genes in DNA repair processes were the most significantly regulated by all AA treatments. Furthermore, response to DNA damage stimulus, apoptosis, and regulation of cell cycle, were also significantly regulated by AA treatment. Among the differentially expressed genes found in the dose-response and time-course studies that were involved in these biological processes, two up-regulated (GADD45B, NAIP), and six down-regulated genes (TP53, PARP1, OGG1, ERCC1, ERCC2, and MGMT) were confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). AA exposure also caused a down-regulation of the gene expression of antioxidant enzymes, such as superoxide dismutase, glutathione reductase, and glutathione peroxidase. Moreover, AA treatment led to increased frequency of DNA strand breaks, 8-hydroxydeoxyguanosine-positive nuclei, and micronuclei in a dose-dependent manner in HK-2 cells, possibly as a result of the inhibition of DNA repair. These data suggest that oxidative stress plays a role in the cytotoxicity of AA. In addition, our results provide insight into the involvement of down-regulation of DNA repair gene expression as a possible mechanism for AA-induced genotoxicity.

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Section: ------------------------------------------------------------supporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

Chen

Chung²,

et al. 2010

Oncol Rep

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“…RNS are produced by the reaction of NO with superoxide and include NO and its derivatives (Wu et al, 2007). NO, as the most important mediator of RNS, has been identified as having three categories of signaling pathways in controlling cell death: (1) Classical signaling involves the selective activation of soluble guanylate cyclase (sGC) (cGMP-dependent protein kinases) (2) Less classical signaling: NO binds to cytochrome c oxidase (CcO) in the mitochondria and its functional consequences (3) Nonclassical signaling alludes to the formation of NO-induced posttranslational modifications (PTMs), especially S-nitrosylation, S-glutathionylation, and tyrosine nitration (Antonio et al, 2011).…”

Section: An Overview Of Reactive Nitrogen Species and Pathwaymentioning

confidence: 99%

Aging, Reactive Nitrogen Species and Myocardial Apoptosis Induced by Ischemia/Reperfusion Injury

Liu¹,

Wang²,

Wang³

et al. 2012

Novel Strategies in Ischemic Heart Disease

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“…However, it was later discovered that AA was a strong carcinogen in mice, rats and humans [5][6][7][8][9][10][11] . Subsequently, AA was found to be a genotoxic mutagen and nephrotoxic [11][12][13][14][15][16][17][18][19][20][21][22][23][24] . During a slimming regimen in Belgium in the early 1990s, AA was proven to be the cause of the so-called aristolochic acid nephropathy (AAN) which was a unique type of rapid progress renal fibrosis associated with the prolonged intake of AA-containing Chinese herbs [9,10,25,26] .…”

Section: Background Of Pharmaceutical and Toxicological Effects Of Aamentioning

confidence: 99%

Recent progress in quantitative analysis of DNA adducts of nephrotoxin aristolochic acid

Yue

Chan

et al. 2009

Sci. China Ser. B-Chem.

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Aristolochic acid (AA), a mixture of structure-related nitrophenanthrene carboxylic acid derivatives derived from Aristolochia spp, is associated with nephrotoxin and carcinogen. AA-DNA adducts induced by reductive metabolic activation of AA were detected in tissues of animals and in patients exposed to AA. The DNA adducts were generally used as biomarkers in toxicological study of AA. In this short review, quantitative analysis of AA-DNA adducts in various in vitro and in vivo systems by using 32 P-postlabelling assay, HPLC-UV, HPLC-radiation monitor, HPLC-FLD, HPLC-ESI/MS and UPLC-MS/MS methods is discussed. The distribution of AA-DNA adducts in various tissues is also summarized.aristolochic acid, DNA adducts, quantitative analysis, short review

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Genotoxic effect and nitrative DNA damage in HepG2 cells exposed to aristolochic acid

Cited by 20 publications

References 35 publications

Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

Aging, Reactive Nitrogen Species and Myocardial Apoptosis Induced by Ischemia/Reperfusion Injury

Recent progress in quantitative analysis of DNA adducts of nephrotoxin aristolochic acid

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