Aristolochic acids.

The evidence for carcinogenicity in humans is based on (1) findings of high rates of urothelial cancer, primarily of the upper urinary tract, among individuals with renal disease who had consumed botanical products containing aristolochic acids and (2) mechanistic studies in humans which demonstrate that aristolochic acids are the carcinogenic agents in these products. Evidence for the carcinogenicity of aristolochic acids was first identified in studies of Belgian patients with nephropathy (progressive interstitial renal fibrosis) related to the consumption of herbal medicines. The patients had consumed Chinese herbal medicines that were inadvertently contaminated with plant species of the genus Aristolochia. Aristolochic acids were considered to be the cause of the nephropathy (now referred to as “aristolochic acid nephro pathy,” or AAN) because (1) the nephropathy developed immediately after ingestion of the herbs, (2) in most cases, the patients had not been exposed to other agents known to be risk factors for nephropathy, (3) aristolochic acids were identified in the herbal products, and (4) aristolochic acid metabolites bound to DNA (AA-DNA adducts) were found in tissues (usually kidney or urothelial tissue) from some of the patients. Over 100 cases of AAN have been reported in Belgium and over 170 cases in other locations, including the United States, Great Britain, Japan, Taiwan, and China (Arlt et al. 2002, NTP 2008). Two prevalence studies in Belgium (at Cliniques Universitaires St.-Luc and Hospital Erasme) reported high rates of urothelial cancer (40% to 46%), mainly of the upper urinary tract, among female AAN patients who had received kidney transplants (Cosyns et al. 1999, Nortier et al. 2000, Nortier and Vanherweghem 2002). This rate of urothelial cancer among AAN patients is much higher than the incidence or prevalence of transitional-cell carcinoma of the urinary tract (i.e., urothelial carcinoma) (0.89% to 4%) reported in several studies of Chinese patients with renal disease, either renal-transplant patients or dialysis patients (Ou et al. 2000, Wu et al. 2004, and Li et al. 2008). Neither prevalence study had an unexposed comparison group. Both studies identified aristolochic acids in the botanical products consumed by the patients, and both studies detected AA-DNA adducts in kidney tissue from the patients, demonstrating that the patients had been exposed to aristolochic acids. In the study at Hospital Erasme, the rate of urothelial cancer was significantly higher among AAN patients who had consumed a high dose of the plant Aristolo­ chia fangchi than among patients who had consumed a lower dose. Furthermore, AAN patients with and without urothelial cancer did not differ significantly with respect to other risk factors for urothelial cancer, such as smoking or the use of analgesics or nonsteroidal anti-inflammatory drugs. A 15-year follow-up study of AAN patients from Hospital Erasme found a rate of upper-urinary-tract urothelial cancer similar to that previously reported by Nortier and colleagues (Lemy et al. 2008). In addition, AAN patients with upper-urinarytract urothelial cancer had an unusually high incidence of urinarybladder urothelial cancer. Additional case reports and clinical investigations of urothelial cancer in AAN patients outside of Belgium support the conclusion that aristolochic acids are carcinogenic (NTP 2008). The clinical studies found significantly increased risks of transitional-cell carcinoma of the urinary bladder and upper urinary tract among Chinese renaltransplant or dialysis patients who had consumed Chinese herbs or drugs containing aristolochic acids, using non-exposed patients as the reference population (Li et al. 2005, 2008). Molecular studies suggest that exposure to aristolochic acids is also a risk factor for Balkan endemic nephropathy (BEN) and upper-urinary-tract urothelial cancer associated with BEN (Grollman et al. 2007). BEN is a chronic tubulointerstitial disease of the kidney, endemic to Serbia, Bosnia, Croatia, Bulgaria, and Romania, that has morphology and clinical features similar to those of AAN. It has been suggested that exposure to aristolochic acids results from consumption of wheat contaminated with seeds of Aristolochia clematitis (Ivic 1970, Hranjec et al. 2005, NTP 2008). AA-DNA adducts were found in kidney tissue from BEN patients and in urothelial and kidney (renal cortical) tissues from BEN patients who had upper-urinary-tract urothelial cancer. Furthermore, A:T to T:A transversion mutations in the p53 tumor-suppressor gene were found in urothelial tumors from BEN patients (Grollman et al. 2007). The available studies are limited in their ability to formally address confounding by other factors that could increase the risk of cancer, and the case-series studies did not include unexposed controls; however, a causal association between exposure to aristolochic acids and human cancer is evidenced by the strength of the association, consistency across studies, dose-response effects, detection of AA-DNA adducts in exposed patients, timing of the exposure and disease, and specific mutations in the p53 gene similar to the A:T to T:A transversions seen in rodents and rodent cell cultures exposed to aristolochic acids. The finding of urothelial cancer among patients who consumed a variety of botanical products from different plant species known to contain aristolochic acids provides additional support for the role of aristolochic acids as the cancer-causing agent in the botanical products. In 2000, the International Agency for Research on Cancer concluded that there was sufficient evidence for the carcinogenicity of herbal remedies containing plant species of the genus Aristolochia in humans (IARC 2002). In 2008, IARC concluded that aristolochic acids also were carcinogenic to humans (Grosse et al. 2009).