Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Arthur P. Grollman, Shinya Shibutani, Masaaki Moriya, Frederick Miller, Lin Wu, Ute Moll, Naomi Suzuki, Andrea Fernandes, Thomas Rosenquist, Zvonimir Medverec, Krunoslav Jakovina, Branko Brdar, Neda Slade, Robert J. Turesky, Angela K. Goodenough, Robert Rieger, Mato Vukelić, Bojan Jelaković

Research output: Contribution to journalArticle

402 Scopus citations

Abstract

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 32P-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.

Original languageEnglish (US)
Pages (from-to)12129-12134
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number29
DOIs
StatePublished - Jul 17 2007
Externally publishedYes

    Fingerprint

Keywords

  • DNA adduct
  • Environmental mutagen
  • Urothelial cancer
  • p53 mutation

Cite this

Grollman, A. P., Shibutani, S., Moriya, M., Miller, F., Wu, L., Moll, U., Suzuki, N., Fernandes, A., Rosenquist, T., Medverec, Z., Jakovina, K., Brdar, B., Slade, N., Turesky, R. J., Goodenough, A. K., Rieger, R., Vukelić, M., & Jelaković, B. (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), 12129-12134. https://doi.org/10.1073/pnas.0701248104