PNAS：马兜铃酸可致肾功能衰竭和癌症发生

马兜铃酸（Aristolochia acid，AA）是救治病人的中草药中的一种组分，目前研究者发现，这种马兜铃酸因为其毒性可以引起个体肾功能衰竭以及上泌尿道癌症。

马兜铃酸（Aristolochia acid，AA）是救治病人的中草药中的一种组分，目前研究者发现，这种马兜铃酸因为其毒性可以引起个体肾功能衰竭以及上泌尿道癌症。研究者的相关研究成果刊登在了近日的国际杂志PNAS上。美国人类健康服务中心的人员发现马兜铃酸是一种强力的肾毒素以及致癌原。近日，研究者Grollman及同事证实AA在巴尔干半岛等国是一种本土肾病的致病因子，而且相关研究也会刊登在杂志Kidney International上。

研究者Grollman表示，我们这项研究的亮点之处在于揭示了一种长期影响个体健康被忽略的疾病，在台湾以及中国和世界上其它国家，长期使用马兜铃属的药物来进行长期的药物治疗必然会对患者的健康带来严重的威胁。在台湾的一项调查中显示，20万随机调查的人群中有1/3的人都在服用马兜铃属植物的药物。研究者又调查了巴尔干半岛上的国家比利时，发现因为服用AA引起的癌症风险正在逐年增加。

研究者从癌症患者中提取DNA进行检测，测定AA代谢产物和DNA之间的结合作用，通过研究其配合作用，即AA和DNA之间的作用，研究者发现，这将会促使基因组DNA的性质改变，而DNA的改变过程在癌症的发展过程中至关重要。

研究者Grollman解释道，他们的分子流行病学研究清楚地阐述了肾皮质中存在的AA-DNA的作用，以及肿瘤组织的特异性突变。他最后强调，我们必须为公众健康建立一个基金，用以制定相关策略来消除因为马兜铃酸所引起的肾脏病变以及癌症的发生。

doi:10.1073/pnas.1119920109
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Aristolochic acid-associated urothelial cancer in Taiwan

Chung-Hsin Chena,b, Kathleen G. Dickmanc,d, Masaaki Moriyac, Jiri Zavadile, Viktoriya S. Sidorenkoc, Karen L. Edwardsf, Dmitri V. Gnatenkod, Lin Wug, Robert J. Tureskyh, Xue-Ru Wui,j, Yeong-Shiau Pua,1, and Arthur P. Grollmanc,d,1

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5′AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.