Aristolochic acid (AA), a potent nephrotoxin and human carcinogen, is a constituent of Aristolochia plants, many of which have been used for medicinal purposes for more than 2000 years. Adopting a molecular epidemiologic approach, we developed chemical and genomic biomarkers to document the contribution of AA to chronic renal disease and urothelial carcinoma of the upper urinary tract (UTUC).  Aristolactam (AL)-DNA adducts persist for decades in renal tissues and can be detected using sensitive mass spectrometric techniques. These adducts, which are resistant to genomic DNA repair, generate a unique pattern of mutations in TP53, characterized by A to T transversions located almost exclusively on the non-transcribed strand. Mutations cluster at acceptor splice sites and at hotspots that are rarely mutated in other cancers. Whole-exome sequencing analysis was used to characterize further the mutational signature associated with AA exposure and to identify driver mutations at the tumor site.  Studies of AA metabolites clarified details of the pathway by which AA is bioactivated to react with DNA; structure-function studies of AA analogs suggest the mechanism underlying AA nephrotoxicity in mice.Use of these sensitive and specific biomarkers enabled us to establish the etiology of Balkan endemic nephropathy, an environmental disease, and to document the carcinogenicity of Aristolochia herbs in Taiwan, where the prevalence of UTUC is the highest in the world. The practice of Chinese herbal medicine in Taiwan mirrors that in China and other Asian countries, an observation with significant implications for global public health. The development and application of sensitive, specific, yet minimally invasive biomarker-based tests to detect AL-DNA adducts and AA-mutated DNA among populations at risk is essential, as UTUC is curable by surgery, if detected early in the course of this disease.

Molecular toxicology of aristolochic acid, a human carcinogen

248th National Meeting (2014)

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