Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Grollman, Arthur P. and Shibutani, Shinya and Moriya, Masaaki and Miller, Fredrick and Wu, Lin and Moll, Ute and Suzuki, Naomi and Fernandes, Andrea and Rosenquist, Thomas and Medverec, Zvonimir and Jakovina, Krunoslav and Brdar, Branko and Slade, Neda and Turesky, Robert J. and Goodenough, Angela K. and Rieger, Robert and Vukelić, Mato and Jelaković, Bojan (2007) Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proceedings of the National Academy of Sciences of the United States of America, 104 (29). pp. 12129-12134. ISSN 0027-8424

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Endemic (Balkan) nephropathy (EN), a devastating renal disease affecting men and women living in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, is characterized by its insidious onset, invariable progression to chronic renal failure and a strong association with transitional cell (urothelial) carcinoma of the upper urinary tract. Significant epidemiologic features of EN include its focal occurrence in certain villages and a familial, but not inherited, pattern of disease. Our experiments test the hypothesis that chronic dietary poisoning by aristolochic acid is responsible for EN and its associated urothelial cancer. Using (32)P-postlabeling/PAGE and authentic standards, we identified dA-aristolactam (AL) and dG-AL DNA adducts in the renal cortex of patients with EN but not in patients with other chronic renal diseases. In addition, urothelial cancer tissue was obtained from residents of endemic villages with upper urinary tract malignancies. The AmpliChip p53 microarray was then used to sequence exons 2-11 of the p53 gene where we identified 19 base substitutions. Mutations at A:T pairs accounted for 89% of all p53 mutations, with 78% of these being A:T --> T:A transversions. Our experimental results, namely, that (i) DNA adducts derived from aristolochic acid (AA) are present in renal tissues of patients with documented EN, (ii) these adducts can be detected in transitional cell cancers, and (iii) A:T --> T:A transversions dominate the p53 mutational spectrum in the upper urinary tract malignancies found in this population lead to the conclusion that dietary exposure to AA is a significant risk factor for EN and its attendant transitional cell cancer.

Item Type: Article
MeSH: Aristolochic Acids - adverse effects - analysis - chemistry ; Balkan Nephropathy - chemically induced - etiology ; Carcinoma, Transitional Cell - pathology ; DNA Adducts - analysis - chemistry ; Female ; Humans ; Kidney - chemistry - pathology ; Male ; Mutation - genetics ; Spectrometry, Mass, Electrospray Ionization ; Tumor Suppressor Protein p53 - genetics ; Urologic Neoplasms - pathology
Departments: Katedra za internu medicinu
Depositing User: Lea Škorić
Status: Published
Grollman, Arthur P.UNSPECIFIED
Shibutani, ShinyaUNSPECIFIED
Moriya, MasaakiUNSPECIFIED
Miller, FredrickUNSPECIFIED
Fernandes, AndreaUNSPECIFIED
Rosenquist, ThomasUNSPECIFIED
Medverec, ZvonimirUNSPECIFIED
Jakovina, KrunoslavUNSPECIFIED
Turesky, Robert J.UNSPECIFIED
Goodenough, Angela K.UNSPECIFIED
Jelaković, BojanUNSPECIFIED
Date: July 2007
Date Deposited: 11 Oct 2007
Last Modified: 23 Sep 2011 16:10
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