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Aristolochic Acid and the Etiology of Endemic (Balkan) Nephropathy

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Aristolochic Acid and the Etiology of Endemic (Balkan) Nephropathy 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 Jakovinaʈ, Branko Brdar**, Neda Slade**, Robert J. Turesky††, Angela K. Goodenough††, Robert Rieger*, Mato Vukelic´ʈ, and Bojan Jelakovic´‡‡§§ *Laboratory of Chemical Biology, Department of Pharmacological Sciences, and ‡Department of Pathology, Stony Brook University, Stony Brook, NY 11794; ¶Department of Urological Surgery and ʈDepartment of Pathology, Josip Bencˇevic´General Hospital, 35000 Slavonski Brod, Croatia; §Roche Molecular Systems, Pleasanton, CA 94588; **Institute Rudjer Bosˇkovic´, 10000 Zagreb, Croatia; ††Division of Environmental Disease Prevention, Wadsworth Center, New York State Department of Health, Albany, NY 12201; ‡‡Department of Nephrology and Arterial Hypertension, Zagreb University School of Medicine and University Hospital Center, 10000 Zagreb, Croatia; and §§Croatian Center for Endemic Nephropathy, 35000 Slavonski Brod, Croatia Edited by Arno G. Motulsky, University of Washington School of Medicine, Seattle, WA, and approved June 8, 2007 (received for review February 9, 2007) Endemic (Balkan) nephropathy (EN), a devastating renal disease a risk factor for both EN and the transitional cell cancer that affecting men and women living in rural areas of Bosnia, Bulgaria, frequently accompanies it. Croatia, Romania, and Serbia, is characterized by its insidious We initiated our research by conducting a pilot epidemiologic onset, invariable progression to chronic renal failure and a strong study in the endemic region of Croatia where bread, the dietary association with transitional cell (urothelial) carcinoma of the staple of the region, is prepared traditionally from flour made upper urinary tract. Significant epidemiologic features of EN in- from locally grown wheat (16). We confirmed earlier observa- clude its focal occurrence in certain villages and a familial, but not tions that Aristolochia clematitis, a plant native to the endemic inherited, pattern of disease. Our experiments test the hypothesis region, often grows in cultivated fields (17–19) where its seeds that chronic dietary poisoning by aristolochic acid is responsible for comingle with wheat grain during the annual harvest (16, 18). EN and its associated urothelial cancer. Using 32P-postlabeling/ We estimate that bread prepared from flour ground from grain PAGE and authentic standards, we identified dA-aristolactam (AL) contaminated by a few seeds of A. clematitis would provide, over and dG-AL DNA adducts in the renal cortex of patients with EN but time, dietary exposure to AA equivalent to that documented for not in patients with other chronic renal diseases. In addition, patients with AAN (16). Thus, residents of the endemic region urothelial cancer tissue was obtained from residents of endemic who ingested home-baked bread prepared from contaminated villages with upper urinary tract malignancies. The AmpliChip p53 grain may be exposed, over a period of years, to toxic amounts microarray was then used to sequence exons 2–11 of the p53 gene of AA (16, 18). where we identified 19 base substitutions. Mutations at A:T pairs After metabolic activation, AA reacts with DNA to form accounted for 89% of all p53 mutations, with 78% of these being covalent dA-aristolactam (AL) and dG-AL adducts (20, 21). The 3 A:T T:A transversions. Our experimental results, namely, that (i) dA-AL adduct persists for an extended period (22), facilitating DNA adducts derived from aristolochic acid (AA) are present in its detection in target tissues. Thus, building on epidemiologic, renal tissues of patients with documented EN, (ii) these adducts can environmental, and agricultural evidence (6, 16–19), we exam- 3 be detected in transitional cell cancers, and (iii) A:T T:A trans- ined renal tissues of EN patients for these biomarkers of versions dominate the p53 mutational spectrum in the upper exposure to AA. Additionally, AL-DNA adducts are known to urinary tract malignancies found in this population lead to the be mutagenic (23–28), leading us to determine the p53 muta- conclusion that dietary exposure to AA is a significant risk factor tional spectrum of transitional cell cancers in patients with EN. for EN and its attendant transitional cell cancer. In this article, we report the detection of dA-AL and dG-AL adducts in the renal cortex of patients with EN and in transitional MEDICAL SCIENCES environmental mutagen ͉ p53 mutation ͉ urothelial cancer ͉ DNA adduct cell cancers of endemic village residents. The p53 mutational spectra of these cancers are dominated by A:T 3 T:A transver- ndemic (Balkan) nephropathy (EN), a chronic tubulointer- sions, resembling the mutational ‘‘signature’’ observed in cul- Estitial disease found in Bosnia, Bulgaria, Croatia, Romania, tured cells and rodents treated with AA (23–28). These findings and Serbia occurs exclusively in farming villages situated in provide support for our guiding hypothesis that dietary exposure valleys of tributaries of the Danube River (1, 2). This striking to AA is a risk factor for EN and that AA-derived DNA adducts geographic distribution has remained constant since the disease initiate the transitional cell cancers associated with this disease. was first described in the late 1950s (3–5). Significant epidemi- ologic features of EN include its focal occurrence in certain villages, a familial but not inherited pattern of disease, initial Author contributions: A.P.G., S.S., F.M., U.M., R.J.T., and B.J. designed research; L.W., N. manifestation after residence in an endemic village for 15 years Suzuki, A.F., T.R., Z.M., K.J., B.B., N. Slade, A.K.G., and R.R. performed research; Z.M., K.J., or more (6), and strong association with upper urinary tract and M.V. contributed new reagents/analytic tools; A.P.G., S.S., M.M., F.M., L.W., K.J., R.J.T., M.V., and B.J. analyzed data; and A.P.G., R.J.T., and B.J. wrote the paper. transitional cell (urothelial) cancer (7). The authors declare no conflict of interest. Despite extensive research conducted over the past 50 years, the etiology of EN remains obscure (8). The potential involve- This article is a PNAS Direct Submission. ment of environmental toxins, including mycotoxins, phytotox- Freely available online through the PNAS open access option. ins, heavy metals, viruses, and trace element deficiencies, has Abbreviations: AA, aristolochic acid (mixture of AA-I and AA-II); AAN, aristolochic acid nephropathy; AL, aristolactam; dA-AL-I, 7-(deoxyadenosin-N6-yl) aristolactam-I; dA-AL-II, been widely explored (9–11), with ochratoxin A being a primary 7-(deoxyadenosin-N6-yl) aristolactam-II; dG-AL, 7-(deoxyguanosin-N2-yl) aristolactam-I; focus of EN research in recent years (12, 13). Our investigations dNs, nucleotides/nucleosides; EN, endemic (Balkan) nephropathy. into this subject were prompted by the striking clinical and †To whom correspondence should be addressed. E-mail: [email protected]. histopathologic similarities between EN and aristolochic acid This article contains supporting information online at www.pnas.org/cgi/content/full/ nephropathy (AAN) (14, 15). This insightful observation gen- 0701248104/DC1. erated the hypothesis guiding our research, namely, that AA is © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0701248104 PNAS ͉ July 17, 2007 ͉ vol. 104 ͉ no. 29 ͉ 12129–12134 Downloaded by guest on September 23, 2021 single dA-AL-I or dG-AL-I adduct were digested in parallel as controls for the 32P-postlabeling/PAGE assay (29). The chemical identity of dA-AL-I- and dA-AL-II-DNA adducts in the renal cortex of this patient was established by mass spectrometry (Fig. 2), with the full product ion spectra for the 7-(deoxyadenosin- N6-yl) aristolactam-I (dA-AL-I) and 7-(deoxyadenosin-N6-yl) aristolactam-II (dA-AL-II) adducts being identical to those of synthetic standards. The signal corresponding to dG-AL was below the level of detection (Ͻ1 adduct per 108 dNs). We estimate that the level of dA-AL-I adducts was much greater (Ϸ70-fold) than that of dA-AL-II, consistent with reports using 32P-postlabeling analysis (22). Fig. 1. Detection of AL-DNA adducts in renal tissues of a patient with AAN. DNA (20 ␮g) was extracted from the renal cortex, medulla, and pelvis of an AL-DNA Adducts in Renal Tissues of Patients with EN. Criteria American woman who developed end-stage renal failure after treatment established by the World Health Organization (30) were used to with an herbal remedy containing Aristolochia. The level of AL-DNA adducts establish the clinical diagnosis of EN. In most cases, the clinical in these tissues was determined by quantitative 32P-postlabeling/PAGE anal- diagnosis was confirmed by the unique renal histopathology; in ysis (29). Samples in lanes 1–3 and 4–6 were excised from the right and left some, the pattern of interstitial fibrosis characteristic of EN was kidneys, respectively. Lanes 1 and 4 are from the renal cortex; lanes 2 and 5, obscured by changes associated with end-stage renal disease. from the renal medulla; and lanes 3 and 6, from the renal pelvis. Oligonucle- otides containing dA-AL-I and dG-AL-I (1 adduct per 106 dNs), digested in Formalin-fixed renal tissues embedded in paraffin blocks were parallel, were used as standards. obtained from four patients who met the diagnostic criteria. Histopathologic examination of these tissues, performed inde- pendently by three renal pathologists, revealed the typical EN Results pattern of dense interstitial fibrosis with minimal inflammation and relative sparing of glomeruli (31). AL-DNA adducts were Identification and Quantitation of AL-DNA Adducts in Human Tissues. detected in all EN patient samples by the 32P-postlabeling/PAGE Prophylactic bilateral nephrectomy was performed, with in- assay, with levels ranging from 0.8 to 5.9 adducts per 107 dNs for formed consent, on an American woman who developed end- dA-AL and 0.2–6.2 adducts per 107 dNs for dG-AL (Fig.
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