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Aristolochic Acid Suppresses DNA Repair and Triggers Oxidative DNA Damage in Human Kidney Proximal Tubular Cells

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Aristolochic Acid Suppresses DNA Repair and Triggers Oxidative DNA Damage in Human Kidney Proximal Tubular Cells 141-153.qxd 27/5/2010 08:46 Ì ™ÂÏ›‰·141 ONCOLOGY REPORTS 24: 141-153, 2010 141 Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells YA-YIN CHEN1,5, JING-GUNG CHUNG2, HSIU-CHING WU3, DA-TIAN BAU1, KUEN-YUH WU1,6, SHUNG-TE KAO1,5, CHIEN-YUN HSIANG4*, TIN-YUN HO1* and SU-YIN CHIANG1* 1School of Chinese Medicine, 2Department of Biological Science and Technology, 3School of Post-Baccalaureate Chinese Medicine, 4Department of Microbiology, China Medical University, Taichung; 5Department of Chinese Medicine, China Medical University Hospital, Taichung; 6Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan Received March 2, 2010; Accepted April 13, 2010 DOI: 10.3892/or_00000839 Abstract. Aristolochic acid (AA), derived from plants of the of the inhibition of DNA repair. These data suggest that Aristolochia genus, has been proven to be associated with oxidative stress plays a role in the cytotoxicity of AA. In aristolochic acid nephropathy (AAN) and urothelial cancer in addition, our results provide insight into the involvement of AAN patients. In this study, we used toxicogenomic analysis down-regulation of DNA repair gene expression as a to clarify the molecular mechanism of AA-induced cyto- possible mechanism for AA-induced genotoxicity. toxicity in normal human kidney proximal tubular (HK-2) cells, the target cells of AA. AA induced cytotoxic effects in Introduction a dose-dependent (10, 30, 90 μM for 24 h) and time- dependent manner (30 μM for 1, 3, 6, 12 and 24 h). The Aristolochic acid (AA), a mixture of structurally-related cells from those experiments were then used for microarray nitrophenanthrene carboxylic acids, was first detected in experiments in triplicate. Among the differentially expressed Aristolochia clematitis in 1943 (1). Aristolochic acid I (AAI) genes analyzed by Limma and Ingenuity Pathway Analysis and Aristolochic acid II (AAII) are the two main active software, we found that genes in DNA repair processes were compounds of plants from the genus Aristolochia. Natural the most significantly regulated by all AA treatments. products containing AA were used in some pharmaceutical Furthermore, response to DNA damage stimulus, apoptosis, preparations as anti-inflammatory agents; moreover, many and regulation of cell cycle, were also significantly regulated formulae containing Aristolochia plants are commonly used by AA treatment. Among the differentially expressed genes as traditional medicine in Eurasia, South America and West found in the dose-response and time-course studies that were Africa (2-4). However, its use gradually declined after Mengs involved in these biological processes, two up-regulated et al reported that it was carcinogenic in rats (5). Most (GADD45B, NAIP), and six down-regulated genes (TP53, countries now ban or severely restrict the use of plants of the PARP1, OGG1, ERCC1, ERCC2, and MGMT) were con- genus Aristolochia based on a multitude of studies that have firmed by quantitative real-time reverse transcription shown that AA is nephrotoxic in humans (6-10). Aristolochic polymerase chain reaction (qRT-PCR). AA exposure also acid nephropathy (AAN) is characterized by initially normal caused a down-regulation of the gene expression of anti- blood pressure, early severe anemia, mild tubular proteinuria, oxidant enzymes, such as superoxide dismutase, glutathione and rapid progression to renal failure within months up to 2 reductase, and glutathione peroxidase. Moreover, AA years (11). The pathology of AAN shows extensive hypo- treatment led to increased frequency of DNA strand breaks, cellular interstitial fibrosis associated with tubular atrophy 8-hydroxydeoxyguanosine-positive nuclei, and micronuclei in and global glomerular sclerosis (12). Urothelial malignancy a dose-dependent manner in HK-2 cells, possibly as a result of upper urinary tract has been found in 40-46% of patients exposed to AA (13,14). Two population-based studies by _________________________________________ Lai et al found that consumption of AA-containing Chinese herbal products was associated with an increased risk of end-stage renal disease and urinary tract cancer in a dose- Correspondence to: Dr Su-Yin Chiang, School of Chinese dependent manner (15,16). This finding is similar to reports Medicine, China Medical University, No 91, Hsueh-Shih Road, Taichung 404, Taiwan that show that high cumulative doses of AA can induce E-mail: [email protected] nephropathy in humans (17) and that cumulative doses >200 grams of ingested Aristolochia is a significant risk factor *Contributed equally for urothelial carcinoma in Belgian AAN patients (13,14). The carcinogenic effects of AA are considered to be Key words: aristolochic acid, DNA repair, oxidative DNA damage associated with the formation of covalent AA-DNA adducts, which have been detected in affected kidneys of Belgian 141-153.qxd 27/5/2010 08:46 Ì ™ÂÏ›‰·142 142 CHEN et al: DNA REPAIR SUPPRESSION BY ARISTOLOCHIC ACID IN HUMAN CELLS patients with AAN (18,19) and in rodent tissues (20,21). seeded in 75T flasks or 25T flasks and incubated for over- Therefore, it is important to study the mechanism of meta- night before AA treatment. Various concentrations of AA bolic activation of AA and the formation of AA-DNA adducts. (10, 30, 90 μM) were exposed to HK-2 cells for 24 h or AAI and AAII are metabolized to reactive intermediates 30 μM AA was exposed for 1, 3, 6, 12 and 24 h. The control that bind covalently to DNA in vitro and in vivo (18,20). cells were placed in equal amounts of water. Experiments on the enzymatic activation of AA by xanthine oxidase, DT-diaphorase, and cytosolic nitroreductase have 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide confirmed that nitroreduction is crucial in the metabolic (MTT) assay. After AA treatment for varied length of time, activation of AA (20). Other studies have shown that AA MTT was added to 75T flasks or 25T flasks to reach the final can be activated via nitroreduction by cytochrome P450 concentration of 0.5 mg/ml. After a 4-h incubation at 37˚C (CYP) 1A1, CYP1A2, and NADPH:CYP reductase (22-26). in the dark, equal volume of 10% SDS (pH 2.0) was AA forms covalent DNA adducts and deoxyadenosine is added to dissolve the MTT formazan. When the MTT the major target of modification. Broschard et al (27) found formazan was dissolved completely, the samples in flasks that dA-AAI, dG-AAI and dA-AAII severely block DNA were transferred to 96-well plates at a volume of 200 μl per replication. AA-adenine adducts have a higher mutagenic well. The absorbance was measured at a test wavelength potential compared with the AA-guanine adducts and of 570 nm and a reference wavelength of 630 nm using a AT➝TA transversion mutation has been found in ras gene microplate reader. The relative survival of cell growth was of AA-exposed rodent tissues and in P53 gene of tissues in calculated by the equation that follows: survival rate (%) = AAN patients. Similarly, in AAN patients, one major (dA- (Absorbance of AA-treated cells - absorbance of medium AAI) and two minor (dG-AAI and dA-AAII) DNA adducts only/Absorbance of untreated cells - absorbance of medium were detected in renal and urinary tissues (13,18,19,28-30). only) x 100%. AA-induced cytotoxicity and genotoxicity have been studied in several biological systems over the past years. RNA isolation and toxicogenomic analysis. Total RNAs were Balachandran et al (31) and Li et al (32) have used a porcine extracted from HK-2 cells collected from the dose and time- proximal tubular epithelial cell line (LLC-PK1) to study course study using RNeasy Mini kit (Qiagen, Valencia, CA). DNA damage, cell cycle perturbations, and cell apoptosis Total RNA was quantified using the Beckman DU800 spectro- induced by AA. Human urinary tract epithelium cells (SV- photometer (Beckman Coulter, Fullerton, CA). Samples with HUC-1), human hepatoma HepG2 cells, and human colo- A260/A280 ratios >1.8 were further evaluated using Aglient rectal cancer cells (HCT 116) (33-35) have also been used to 2100 Bioanalyzer (Agilent Technologies, Santa Clara, study the cytotoxicity or genotoxicity of AA. Chen et al (36) CA). The RNA samples with an RNA integrity number >8.0 have shown that more cancer-related genes were significantly were subjected to microarray analysis. altered in target (kidney) tissues than in non-target (liver) Microarray analysis was performed in triplicate as tissues in AA-treated rats, suggesting that studies on the described previously (37). Briefly, fluorescence-labeled RNA toxic effects of AA should be conducted in renal cells. targets were prepared from 5 μg of total RNA samples using In this study, we used toxicogenomic analysis to inves- MessageAmp™ aRNA kit (Ambion, Austin, TX) and Cy5 tigate the toxic effects of AA in normal human proximal dye (Amersham Pharmacia, Piscataway, NJ). Triplicate tubular (HK-2) cells, the target cells of AA. We then tried to fluorescent targets were hybridized overnight to the Human elucidate the molecular mechanism of AA-induced toxicity Whole Genome OneArray™ (Phalanx Biotech Group, by applying microarray analysis to explore the changes in Hsinchu, Taiwan), and non-specific targets were washed by gene expression patterns in cells exposed to AA. Our results three different washing steps, and the slides were dried by indicate that the decreased expression of DNA repair genes centrifugation and immediately scanned by an Axon 4000 may contribute to the observed increase in 8-OHdG and scanner (Molecular Devices, Sunnyvale, CA). The Cy5 fluo- micronuclei formation in HK-2 cells and may partly explain rescent intensity of each spot was analyzed by genepix 4.1 the genotoxic effects of AA. software (Molecular Devices). The signal intensity of each spot was corrected by subtracting background signals in Materials and methods the surrounding area.
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