Grollman Arthur P, Shibutani Shinya, Moriya Masaaki, Miller Frederick, Wu Lin, Moll Ute, Suzuki Naomi, Fernandes Andrea, Rosenquist Thomas, Medverec Zvonimir, Jakovina Krunoslav, Brdar Branko, Slade Neda, Turesky Robert J, Goodenough Angela K, Rieger Robert, Vukelić Mato, Jelaković Bojan
Laboratory of Chemical Biology, Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12129-34. doi: 10.1073/pnas.0701248104. Epub 2007 Jul 9.
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.
地方性（巴尔干）肾病（EN）是一种严重的肾脏疾病，影响着波斯尼亚、保加利亚、克罗地亚、罗马尼亚和塞尔维亚农村地区的男女。其特点是发病隐匿，不可避免地进展为慢性肾衰竭，并且与上尿路移行细胞（尿路上皮）癌密切相关。EN的重要流行病学特征包括其在某些村庄的局部发生以及家族性但非遗传性的疾病模式。我们的实验检验了这样一个假设，即马兜铃酸引起的慢性饮食中毒是EN及其相关尿路上皮癌的病因。通过（32）P后标记/PAGE和标准品，我们在EN患者的肾皮质中鉴定出了dA-马兜铃内酰胺（AL）和dG-AL DNA加合物，而在其他慢性肾病患者中未检测到。此外，从地方性村庄患有上尿路恶性肿瘤的居民身上获取了尿路上皮癌组织。然后使用AmpliChip p53微阵列对p53基因的外显子2 - 11进行测序，我们鉴定出了19个碱基替换。A:T对处的突变占所有p53突变的89%，其中78%为A:T --> T:A颠换。我们的实验结果，即（i）在有记录的EN患者的肾组织中存在源自马兜铃酸（AA）的DNA加合物，（ii）这些加合物可在移行细胞癌中检测到，以及（iii）A:T --> T:A颠换在该人群中发现的上尿路恶性肿瘤的p53突变谱中占主导地位，得出结论：饮食中接触AA是EN及其伴随的移行细胞癌的一个重要危险因素。
