Arlt Volker M, Stiborova Marie, Schmeiser Heinz H
Section of Molecular Carcinogenesis, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Mutagenesis. 2002 Jul;17(4):265-77. doi: 10.1093/mutage/17.4.265.
The old herbal drug aristolochic acid (AA), derived from Aristolochia spp., has been associated with the development of a novel nephropathy, designated aristolochic acid nephropathy (AAN), and urothelial cancer in AAN patients. There is clear evidence that the major components of the plant extract AA, aristolochic acid I (AAI) and aristolochic acid II (AAII), both nitrophenanthrene carboxylic acids, are genotoxic mutagens forming DNA adducts after metabolic activation through simple reduction of the nitro group. Several mammalian enzymes have been shown to be capable of activating both AAI and AAII in vitro and in cells. The activating metabolism has been elucidated and is consistent with the formation of a cyclic nitrenium ion with delocalized charge leading to the preferential formation of purine adducts bound to the exocyclic amino groups of deoxyadenosine and deoxyguanosine. The predominant DNA adduct in vivo, 7-(deoxyadenosin-N(6)-yl)aristolactam I (dA-AAI), which is the most persistent of the adducts in target tissue, is a mutagenic lesion leading to AT-->TA transversions in vitro. This transversion mutation is found at high frequency in codon 61 of the H-ras oncogene in tumours of rodents induced by AAI, suggesting that dA-AAI might be the critical lesion in the carcinogenic process in rodents. DNA-binding studies confirmed that both AAs bind to the adenines of codon 61 in the H-ras mouse gene and preferentially to purines in the human p53 gene. In contrast, the molecular mechanism of renal interstitial fibrosis in humans after chronic administration of AA remains to be explored. However, preliminary findings suggest that DNA damage by AA is not only responsible for the tumour development but also for the destructive fibrotic process in the kidney. It is concluded that there is significant evidence that AA is a powerful nephrotoxic and carcinogenic substance with an extremely short latency period, not only in animals but also in humans. In particular, the highly similar metabolic pathway of activation and resultant DNA adducts of AA allows the extrapolation of carcinogenesis data from laboratory animals to the human situation. Therefore, all products containing botanicals known to or suspected of containing AA should be banned from the market world wide.
源自马兜铃属植物的传统草药马兜铃酸（AA）与一种新型肾病——马兜铃酸肾病（AAN）的发生有关，并且与AAN患者的尿路上皮癌有关。有明确证据表明，植物提取物AA的主要成分马兜铃酸I（AAI）和马兜铃酸II（AAII），这两种硝基菲羧酸都是基因毒性诱变剂，通过硝基的简单还原进行代谢活化后会形成DNA加合物。已表明几种哺乳动物酶在体外和细胞中都能够激活AAI和AAII。其活化代谢过程已得到阐明，并且与形成具有离域电荷的环状氮鎓离子一致，从而导致优先形成与脱氧腺苷和脱氧鸟苷的环外氨基结合的嘌呤加合物。体内主要的DNA加合物7-(脱氧腺苷-N(6)-基)马兜铃内酰胺I（dA-AAI），是靶组织中最持久的加合物，是一种诱变损伤，在体外会导致AT→TA颠换。这种颠换突变在由AAI诱导的啮齿动物肿瘤中的H-ras癌基因第61密码子处高频出现，这表明dA-AAI可能是啮齿动物致癌过程中的关键损伤。DNA结合研究证实，两种马兜铃酸都与H-ras小鼠基因第61密码子的腺嘌呤结合，并且优先与人p53基因中的嘌呤结合。相比之下，长期服用AA后人类肾间质纤维化的分子机制仍有待探索。然而，初步研究结果表明，AA造成的DNA损伤不仅是肿瘤发生的原因，也是肾脏破坏性纤维化过程的原因。结论是，有充分证据表明AA是一种强大的肾毒性和致癌物质，潜伏期极短，不仅在动物中如此，在人类中也是如此。特别是，AA高度相似的活化代谢途径和由此产生的DNA加合物使得能够将致癌数据从实验动物外推至人类情况。因此，所有已知或疑似含有AA的植物性产品都应在全球市场上被禁止。
