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Open AccessReview

DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer

Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-12843 Prague 2, Czech Republic
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King’s College London, London SE1 9NH, UK
NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King’s College London in partnership with Public Health England, London SE1 9NH, UK
Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(10), 2144;
Received: 4 September 2017 / Revised: 29 September 2017 / Accepted: 11 October 2017 / Published: 14 October 2017
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading to specific A:T to T:A transversion mutations (mutational signature) in AAN/BEN-associated tumours, which are otherwise rare in individuals with UCC not exposed to AA. Therefore, such DNA damage produced by AA-DNA adducts is one rare example of the direct association of exposure and cancer development (UUC) in humans, confirming that the covalent binding of carcinogens to DNA is causally related to tumourigenesis. Although aristolochic acid I (AAI), the major component of the natural plant extract AA, might directly cause interstitial nephropathy, enzymatic activation of AAI to reactive intermediates capable of binding to DNA is a necessary step leading to the formation of AA-DNA adducts and subsequently AA-induced malignant transformation. Therefore, AA-DNA adducts can not only be utilized as biomarkers for the assessment of AA exposure and markers of AA-induced UUC, but also be used for the mechanistic evaluation of its enzymatic activation and detoxification. Differences in AA metabolism might be one of the reasons for an individual’s susceptibility in the multi-step process of AA carcinogenesis and studying associations between activities and/or polymorphisms of the enzymes metabolising AA is an important determinant to identify individuals having a high risk of developing AA-mediated UUC. View Full-Text
Keywords: aristolochic acid; carcinogenicity; mutagenesis; nephrotoxicity; DNA adduct formation aristolochic acid; carcinogenicity; mutagenesis; nephrotoxicity; DNA adduct formation
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Stiborová, M.; Arlt, V.M.; Schmeiser, H.H. DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer. Int. J. Mol. Sci. 2017, 18, 2144.

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