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

Abstract

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.

Recognition of the toxicity of aristolochic acid

“…In addition, AA exposure has been frequently linked to urothelial malignancies, and AA was classified as a human class I carcinogen by the WHO's International Agency for Research on Cancer (IARC) in 2002 . In 2012, AA was classified by the IARC as a human carcinogen (group 1) that acts via a genotoxic mechanism …”

“…A previous study detected a A:T‐to‐T:A mutation in codon 139 (Lys‐Stop) of exon 5 in the p53 gene in DNA isolated from an AAN‐associated urothelial carcinoma . Because the A:T‐to‐T:A transversions found in TP53 correspond to the known mutagenic specificity of AA, it has been suggested that these AA‐induced TP53 gene transversion mutations in urothelial cells can be used as mechanistically relevant biomarkers of AA exposure and of specific AA‐DNA adducts found in the renal tissue of AAN patients …”

“…10 In 2012, AA was classified by the IARC as a human carcinogen (group 1) that acts via a genotoxic mechanism. 11 In 2003, the China Food and Drug Administration (CFDA) issued a notice for the abolition of the medical standards associ- 12 Since 2003, some AA-containing herbal remedies have been officially prohibited in Taiwan, 6 and AA-containing herbs were withdrawn from the market by the local health authority of Hong Kong in June 2004. 13 In China, the government and various research institutes have re-evaluated the usage and circulation of AA-containing herbs and updated regulations and solutions accordingly.…”

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches

“…Thus, the use of plants or remedies containing AA has been banned in several countries [19][20][21]. However, due to the worldwide distribution of Aristolochia plant species and the great use of herbal medicines in some regions, individuals are still exposed to AA [16,22,23]. In this context, research to understand the molecular mechanisms of AA-induced nephrotoxicity might allow for finding out efficient protective mechanisms or eventually, to provide a model of study for investigating drug-induced organ toxicity.…”

DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans

“…A number of chemicals and lifestyle factors have been linked to certain types of cancers. For example, chemicals in cigarette smoke, such as polycyclic aromatic hydrocarbons (PAHs), are linked to lung cancer; occupational exposures to aromatic amines are linked to bladder cancer; traditional Chinese herbal medicines containing aristolochic acids (AA) are linked to upper urothelial cancer; and aflatoxin B 1 (AFB 1 ) which is produced by fungi on agricultural crops, is a risk factor for liver cancer . Therefore, the identification and quantitation of DNA adducts are first important steps in elucidating the potential role of a genotoxic chemical in the etiology of cancer .…”