title: Aristolochic acid and the etiology of endemic (Balkan) nephropathy.
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 (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.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA. apg@pharm.stonybrook.edu
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
authors.forename: Masaaki
authors.initials: M
authors.lastname: Moriya
authors.forename: Frederick
authors.initials: F
authors.lastname: Miller
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Ute
authors.initials: U
authors.lastname: Moll
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Andrea
authors.initials: A
authors.lastname: Fernandes
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenquist
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Medverec
authors.forename: Krunoslav
authors.initials: K
authors.lastname: Jakovina
authors.forename: Branko
authors.initials: B
authors.lastname: Brdar
authors.forename: Neda
authors.initials: N
authors.lastname: Slade
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.forename: Angela K
authors.initials: AK
authors.lastname: Goodenough
authors.forename: Robert
authors.initials: R
authors.lastname: Rieger
authors.forename: Mato
authors.initials: M
authors.lastname: Vukelić
authors.forename: Bojan
authors.initials: B
authors.lastname: Jelaković
mesh_terms: D034341:Aristolochic Acids / Q000009:adverse effects* / Q000032:analysis / Q000737:chemistry; D001449:Balkan Nephropathy / Q000139:chemically induced* / Q000209:etiology*; D002295:Carcinoma, Transitional Cell / Q000473:pathology; D018736:DNA Adducts / Q000032:analysis / Q000737:chemistry; D005260:Female; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D021241:Spectrometry, Mass, Electrospray Ionization; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014571:Urologic Neoplasms / Q000473:pathology
chemical_list: D034341:Aristolochic Acids; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; C000228:aristolochic acid I