Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer.
نویسندگان
چکیده
Balkan endemic nephropathy (BEN) is found in certain rural areas of the Balkans and affects at least 25,000 inhabitants. Of the many hypotheses on BEN, the Aristolochia hypothesis has recently gained ground substantiated by the investigations on aristolochic acid nephropathy (AAN). On both clinical and morphological grounds, AAN is very similar to BEN. That exposure to aristolochic acid (AA) of individuals living in endemic areas through consumption of bread made with flour contaminated with seeds of Aristolochia clematitis is responsible for BEN is an old hypothesis, but one which is fully consistent with the unique epidemiologic features of BEN. Here, we propose an approach to investigate AA-induced mutagenesis in BEN that can provide molecular clues to the aetiology of its associated urothelial cancer. The molecular mechanism of AA-induced carcinogenesis demonstrates a strong association between DNA adduct formation, mutation pattern and tumour development. A clear link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients from different endemic areas becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT --> TA transversion mutations as has already been demonstrated in the human p53 gene of immortalized cells after exposure to AAI and urothelial tumours from BEN patients in Croatia. Moreover, the detection of AA-specific DNA adducts in renal tissue of a number of BEN patients and individuals living in areas endemic for BEN in Croatia provides new evidence that chronic exposure to AA is a risk factor for BEN and its associated cancer.
منابع مشابه
Role of environmental toxins in endemic (Balkan) nephropathy. October 2006, Zagreb, Croatia.
An international symposium, held in Zagreb, Croatia, in October 2006, brought together basic scientists and clinical investigators engaged in research on endemic (Balkan) nephropathy, a chronic renal tubulointerstitial disease of previously unknown cause that often is accompanied by upper urinary tract urothelial cancer. Although this disease is endemic in rural areas of Bosnia, Bulgaria, Croat...
متن کاملBalkan Endemic Nephropathy and Associated Urothelial Cancer: Current Status and Future Research
_______________________________ Correspondence to: Goce B Spasovski, MD, PhD, Department of Nephrology, Clinical Center Skopje, Vodnjanska 17, 1000 Skopje, Macedonia, Fax: +389 2 3220 935 or +389 2 3231 501, E-mail: [email protected] Balkan Endemic Nephropathy and Associated Urothelial Cancer: Current Status and Future Research V. Stefanovic Institute of Nephrology and Hemodialysis, Faculty of...
متن کاملA historical overview of Balkan Endemic Nephropathy (BEN) in relation to published hypotheses.
Balkan Endemic Nephropathy occurs with a high rate of prevalence in Serbia, Bulgaria, Romania, Bosnia and Herzegovina, and Croatia. The first cases described in Bulgaria, Serbia and Romania date to the late 1950s and early 1960s. BEN has been characterized to date as a chronic, slowly progressive familial tubular interstitial renal disease of unknown aetiology. The disease is characterized by i...
متن کاملDNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer
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...
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ورودعنوان ژورنال:
- Carcinogenesis
دوره 28 11 شماره
صفحات -
تاریخ انتشار 2007