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Species of Aristolochia are used as herbal medicines worldwide. They cause aristolochic acid nephropathy (AAN), a devastating disease associated with kidney failure and renal cancer. Aristolochic acids I and II (1 and 2) are considered to be responsible for these nephrotoxic and carcinogenic effects. A wide range of other aristolochic acid analogues (AAAs) exist, and their implication in AAN may have been overlooked. An LC-MS- and (1)H NMR-based metabolomic analysis was carried out on 43 medicinally used Aristolochia species. The cytotoxicity and genotoxicity of 28 Aristolochia extracts were measured in human kidney (HK-2) cells. Compounds 1 and 2 were found to be the most common AAAs. However, AA IV (3), aristolactam I (4), and aristolactam BI (5) were also widespread. No correlation was found between the amounts of 1 or 2 and extract cytotoxicity against HK-2 cells. The genotoxicity and cytotoxicity of the extracts could be linked to their contents of 5, AA D (8), and AA IIIa (10). These results undermine the assumption that 1 and 2 are exclusively responsible for the toxicity of Aristolochia species. Other analogues are likely to contribute to their toxicity and need to be considered as nephrotoxic agents. These findings facilitate understanding of the nephrotoxic mechanisms of Aristolochia and have significance for the regulation of herbal medicines.

Covering: 1960 to 2013. Aristolochic acids are known for causing aristolochic acid nephropathy, a renal fibrosis often associated with urothelial carcinoma. Aristolochic acid I and II are considered to be the cause of these nephrotoxic and carcinogenic effects. However a variety of aristolochic acid analogues, including aristolactams and 4,5-dioxoaporphines have been reported. Their implications in aristolochic acid nephropathy have possibly been overlooked. In this report, in vivo and in vitro toxicity and mutagenicity of these three classes of compounds are discussed. Furthermore, the review gives an update of aristolochic acids, aristolactams and 4,5-dioxoaporphines reported between 2003 and 2013 and their biological activities.

Ethnopharmacological Relevance: Species of Aristolochia are associated with aristolochic acid nephropathy (AAN), a renal interstitial fibrosis and upper urinary tract cancer (UUC). Aristolochic acid nephropathy has been reported in ten countries but its true incidence is unknown and most likely underestimated. By combining an ethnobotanical and phytochemical approach we provide evidence for the risk of AAN occurring in Bangladesh. More specifically, we assess the intra-specific variation of aristolochic acid analogues in medicinally used Aristolochia indica samples from Bangladesh., Materials and Methods: Ethnobotanical information was collected from 16 kavirajes (traditional healers) in different study locations in Bangladesh. Plant samples were obtained from native habitats, botanical gardens, herbal markets and pharmaceutical companies. The samples were extracted using 70% methanol and were analysed using LC-DAD-MS and (1)H-NMR., Results: Roots as well as leaves are commonly used for symptoms such as snake bites and sexual problems. Among the informants knowledge about toxicity or side effects is very limited and Aristolochia indica is often administered in very high doses. Replacement of Aristolochia indica with other medicinal plants such as Rauvolfia serpentina (L.) Benth. ex Kurz was common. Aristolochia indica samples contained a variety of aristolochic acid analogues such as aristolochic acid I, aristolochic acid II, cepharadione A and related compounds., Conclusions: AAN cases are likely to occur in Bangladesh and more awareness needs to be raised about the health risks associated with the use of Aristolochia indica and other species of Aristolochia as herbal medicines., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.

Aims of the Study: More than 100 cases of nephropathy over the last 10 years caused by the systemic and longer term application of Chinese snakeroot (Aristolochia fangchi) highlighted the risk of using preparations which contain aristolochic acids. On the other hand anecdotal evidence highlights the widespread use of Aristolochia species (Aristolochiaceae) in many regions of the world. Therefore, it was our objective to systematically assess the scientific literature available on the local and traditional use of Aristolochia spp. on a worldwide scale. Our review identifies core species which need to be investigated and which may need monitoring (esp. in national and international trade)., Methods: An extensive review of the literature available in libraries in London on the uses of species of Aristolochia was undertaken. Relevant information was extracted and entered into a database for analysis., Results: Based on the assessment of 566 reference sources 685 individual sets of data were recorded. Seven species--Aristolochia indica L. (Asia), Aristolochia serpentaria L. (North America), Aristolochia debilis Sieb & Zucch. (China), Aristolochia acuminata Lam (India), Aristolochia trilobata L. (Central/South America, Caribbean), Aristolochia clematitis L. (Europe) and Aristolochia bracteolata Lam. (Africa)--are reported widely as being used medicinally. The medical uses vary, but of particular interest are uses in case of gastrointestinal problems, which is likely to result in repeated exposure to the botanical drugs by an individual. About half of all records relate to uses of Aristolochia species in Asia, one-third to the Americas, a continent which has so far received practically no attention in terms of assessing the risk of using species of Aristolochia. Of the 99 species (plus several identified at genus level only) for which we were able to summarise ethnobotanical information, preliminary phytochemical information is only available for 24 species and some of the most common ones including Aristolochia acuminata have so far not been studied phytochemically., Conclusions: Species of Aristolochia are used medicinally in many regions of the world and both from an ethnopharmacological and a public health perspective this poses a risk. A systematic assessment of the content of aristolochic acids in the most widely used species is needed to evaluate whether their uses pose a potential health risk. In China and Europe species of Aristolochia have been associated with nephropathy and it is important to evaluate whether nephropathy occurs in other parts of the world, especially India and Central America where the use of species of Aristolochia are reported to be commonly used in traditional medicine.

Targeted liquid chromatography/serial mass spectrometry (LC/MS/MS) analysis, using a quadrupole ion-trap mass spectrometer, permitted the detection of aristolochic acids I and II in crude 70% methanol extracts of multi-component herbal remedies without any clean-up or concentration stages. The best ionisation characteristics were obtained using atmospheric pressure chemical ionisation (APCI) and by including ammonium ions in the mobile phase. Limits of detection for aristolochic acids were influenced by the level of interference created by other components in the sample matrix. They were determined to be between 250 pg and 2.5 ng on-column within a matrix containing compounds extracted from 2 mg of herbal remedy. With a herbal remedy that only permitted the higher limit of detection, this sensitivity was sufficient to detect the aristolochic acids extracted from 0.1% dry weight of Aristolochia manshuriensis included in the preparation., (Copyright 2002 John Wiley & Sons, Ltd.)