Aristolochic acid and the etiology of endemic (Balkan) nephropathy.
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.
Grollman
Arthur P
AP
Laboratory of Chemical Biology, Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA. apg@pharm.stonybrook.edu
Shibutani
Shinya
S
Moriya
Masaaki
M
Miller
Frederick
F
Wu
Lin
L
Moll
Ute
U
Suzuki
Naomi
N
Fernandes
Andrea
A
Rosenquist
Thomas
T
Medverec
Zvonimir
Z
Jakovina
Krunoslav
K
Brdar
Branko
B
Slade
Neda
N
Turesky
Robert J
RJ
Goodenough
Angela K
AK
Rieger
Robert
R
Vukelić
Mato
M
Jelaković
Bojan
B
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
D034341:Aristolochic Acids; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; C000228:aristolochic acid I