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.

• Keywords
• DNA adduct formation, aristolochic acid, carcinogenicity, mutagenesis, nephrotoxicity,
• MeSH
• DNA Adducts metabolism   MeSH
• Balkan Nephropathy etiology   metabolism   MeSH
• Biomarkers * MeSH
• Carcinogens chemistry   metabolism   MeSH
• Aristolochic Acids chemistry   metabolism   MeSH
• Humans MeSH
• Disease Susceptibility MeSH
• Cell Transformation, Neoplastic genetics   metabolism   MeSH
• Urologic Neoplasms etiology   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• DNA Adducts MeSH
• Biomarkers * MeSH
• Carcinogens MeSH
• Aristolochic Acids MeSH

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.

• Keywords
• Aristolochic acid, Aristolochic acid nephropathy, Balkan endemic nephropathy, Disease aetiology, Environmental and genetic factors, Upper urothelial cancer,
• MeSH
• Aristolochia chemistry   growth & development   toxicity   MeSH
• Balkan Nephropathy chemically induced   epidemiology   physiopathology   prevention & control   MeSH
• Diet adverse effects   MeSH
• Endemic Diseases * MeSH
• Confounding Factors, Epidemiologic MeSH
• Carcinogens, Environmental analysis   toxicity   MeSH
• Food Contamination * prevention & control   MeSH
• Aristolochic Acids analysis   toxicity   MeSH
• Kidney drug effects   physiopathology   MeSH
• Drug Resistance MeSH
• Humans MeSH
• Evidence-Based Medicine * MeSH
• Flour adverse effects   analysis   MeSH
• Plant Weeds chemistry   growth & development   toxicity   MeSH
• Prevalence MeSH
• Triticum growth & development   MeSH
• Risk MeSH
• Seeds growth & development   MeSH
• Urologic Neoplasms chemically induced   epidemiology   physiopathology   prevention & control   MeSH
• Crops, Agricultural growth & development   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Europe, Eastern epidemiology   MeSH
• Names of Substances
• aristolochic acid I MeSH Browser
• Carcinogens, Environmental MeSH
• Aristolochic Acids MeSH