Visit websites selling homeopathic remedies, and sooner or later you will find the virtues of extracts of Aristolochia clematitis extolled. The dark side of this plant's biochemical products is examined by Arthur Grollman, Bojan Jelaković and colleagues in Proceedings of the National Academy of Sciences (A. P. Grollman et al. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0701248104). They provide a strong case that the aristolochic acid produced by A. clematitis is the cause of endemic (Balkan) nephropathy.
This disease results in kidney failure and is associated with cancer of the upper urinary tract. Its name stems from its incidence in farming communities along tributaries of the Danube. Here, as Grollman et al. confirmed in their early work done in Croatia, the plant grows in wheat fields and its seeds become mixed with wheat grains during harvesting — and so can contaminate the flour that is subsequently baked into bread.
The authors' investigations were prompted by similarities between endemic nephropathy and a condition called aristolochic acid nephropathy, which was identified in a group of women in Belgium and attributed to their use of herbal products as part of a slimming regime. Aristolochic acid reacts with DNA, and forms tell-tale biomarkers that can be used as indicators of exposure to the substance.
These biomarkers indeed turned out to be present in Croatian patients with endemic nephropathy, and malignancies of the upper urinary tract, who had long inhabited villages likely to be subject to dietary contamination. They were not seen in patients with other types of kidney disease.
Grollman et al. then went further, delving into the mutational background of the cancers. They focused on the tumour-suppressor protein p53, which helps protect the genome against damage. Here they identified a large proportion of switches of the adenine–thymine nucleotide coupling in DNA to thymine–adenine. This mutational 'fingerprint' is also seen in cultured cells and in rodents treated with aristolochic acid. All in all, the authors' detective work provides enough evidence to put A. clematitis in the dock, if not to allow an outright conviction.
Other causes of endemic nephropathy have been considered over the years, including one that echoes the notorious case of ergotism. This disorder was eventually attributed to the action of toxins produced by fungal infection of cereals. A fungal toxin, ochratoxin A, has likewise been proposed as the agent behind endemic nephropathy, but the authors find the case for that to be weak. However, they estimate that only about 1 in 20 people exposed to high levels of aristolochic acid develop overt disease. They conclude, then, that there must be a large genetic component to susceptibility, and investigations of that aspect will shortly be under way.
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Lincoln, T. Danger in the diet. Nature 448, 148 (2007). https://doi.org/10.1038/448148a