Correspondence
Aristolochic Acid, an Herbal Carcinogen, Sold on the Web after FDA Alert
N Engl J Med 2003; 349:1576-1577October 16, 2003
- Article
To the Editor:
In 2001, the Food and Drug Administration (FDA) issued warnings and an import alert that herbal products are unsafe if they contain or are suspected to contain aristolochic acid.1 A report in the Journal in 2000 described a cohort of 105 patients in whom rapidly progressive nephropathy developed after they had been given an herbal weight-loss product containing aristolochic acid by a Belgian clinic.2 Because of a suspected association between aristolochic acid and urothelial carcinoma, 39 patients with end-stage renal disease underwent prophylactic removal of the kidneys and ureters; urothelial carcinoma was diagnosed in 18 of them. Aristolochic acid nephropathy has been reported in eight other countries, and associated urinary tract cancer has been reported in two.3 The International Agency for Research on Cancer classifies products containing aristolochia species as human carcinogens.4
Despite the actions of the FDA, in 2003 we identified 19 products containing aristolochic acid and 95 products suspected to contain aristolochic acid for sale on the Web. These products and approximately 100 related Web sites are listed on the Web at http://potency.berkeley.edu/aristolochicacid.html. These herbal products should not be available but are sold on U.S. Web sites for gastrointestinal symptoms, weight loss, cough, and immune stimulation.
The toxicologic evidence of the risks associated with aristolochic acid is strong. In 1982, tumors were rapidly induced in rats at low doses5; aristolochic acid is among the most potent 2 percent of the carcinogens in our Carcinogenic Potency Database.6 It is mutagenic, forms DNA adducts in humans, and is carcinogenic in mice.3 In rabbits, aristolochic acid induces nephrotoxic effects, the same DNA adducts in kidney as in humans, and urothelial tumors.3
The availability of aristolochic acid–containing products on the Web two years after an FDA alert was issued reveals a serious flaw in the safety protection afforded the public. Under the Dietary Supplement Health Education Act, herbal products do not require FDA approval of efficacy or safety before marketing, and products are not registered. In addition, the Web is a marketing tool with low barriers to entry (anyone can set up a Web site inexpensively). The failure to protect the public from the imminent hazard of aristolochic acid indicates that there is an urgent need to remove these products from the Web and to develop a policy that addresses Web sales of hazardous herbal products.
6 ReferencesLois Swirsky Gold, Ph.D.
Thomas H. Slone, M.S.
University of California, Berkeley, Berkeley, CA 94720
cpdb@potency.berkeley. edu 1
Food and Drug Administration. Dietary supplements: aristolochic acid. (Accessed September 25, 2003, at http://www.cfsan.fda.gov/~dms/ds-bot.html.)
2
Nortier JL ,Muniz Martinez M-C ,Schmeiser HH , et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-1692
Full Text | Web of Science | Medline3
Arlt VM ,Stiborova M ,Schmeiser HH . Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 2002;17:265-277
CrossRef | Web of Science | Medline4
Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. Vol. 82 of IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Lyons, France: IARC Press, 2002.
5
Mengs U ,Lang W ,Poch J-A . The carcinogenic action of aristolochic acid in rats. Arch Toxicol 1982;51:107-119
CrossRef | Web of Science6
Gold LS, Zeiger E, eds. Handbook of carcinogenic potency and genotoxicity databases. Boca Raton, Fla.: CRC Press, 1997. (Also available at http://potency.berkeley.edu/.)
- Citing Articles (25)
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Peter Greaves. 2012. Urinary Tract. , 537-614.
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Joanne Barnes. 2011. Adverse Drug Reactions and Pharmacovigilance of Herbal Medicines. , 645-683.
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Ying-Yong Zhao, Li Zhang, Jia-Rong Mao, Xiao-Hong Cheng, Rui-Chao Lin, Yongmin Zhang, Wen-Ji Sun. (2011) Ergosta-4,6,8(14),22-tetraen-3-one isolated from Polyporus umbellatus prevents early renal injury in aristolochic acid-induced nephropathy rats. Journal of Pharmacy and Pharmacology 63:12, 1581-1586
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Xiang Xue, Li-Kun Gong, Kazuya Maeda, Yang Luan, Xin-Ming Qi, Yuichi Sugiyama, Jin Ren. (2011) Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I. Molecular Pharmaceutics111020094717003
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Feng-Yih Yu, Ting-Shuan Wu, Ting-Wei Chen, Biing-Hui Liu. (2011) Aristolochic acid I induced oxidative DNA damage associated with glutathione depletion and ERK1/2 activation in human cells. Toxicology in Vitro 25:4, 810-816
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Volker M. Arlt, Jie Zuo, Kristina Trenz, Candice A. Roufosse, Graham M. Lord, Joelle L. Nortier, Heinz H. Schmeiser, Monica Hollstein, David H. Phillips. (2011) Gene expression changes induced by the human carcinogen aristolochic acid I in renal and hepatic tissue of mice. International Journal of Cancer 128:1, 21-32
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Chiao-Shih Tseng, Shih-Ming Chen, Shu-Chen Chien, Kuang-Yang Hsu. (2011) Pharmacokinetics of p-Aminohippuric Acid and Inulin in Rabbits with Aristolochic Acid Nephropathy. Advances in Pharmacological Sciences 2011, 1-7
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Yang Yang, Juan Chen, Yan-Ping Shi. (2010) Determination of aristolochic acid in urine using hollow fiber liquid-phase microextraction combined with high-performance liquid chromatography. Biomedical Chromatography 24:12, 1350-1355
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Nadiya Bakhiya, Volker M. Arlt, Andrew Bahn, Gerhard Burckhardt, David H. Phillips, Hansruedi Glatt. (2009) Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy. Toxicology 264:1-2, 74-79
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Thomas Y.K. Chan. (2009) Potential Risks Associated with the Use of Herbal Anti-Obesity Products. Drug Safety 32:6, 453-456
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Wan Chan, Wing Tat Poon, Yan-Wo Chan, King-Yi Wan, Zongwei Cai. (2009) A new approach for the sensitive determination of DNA adduct of aristolochic acid II by using high-performance liquid chromatography with fluorescence detection. Journal of Chromatography B 877:10, 848-852
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Wan Chan, Hao Yue, Wing Tat Poon, Yan-Wo Chan, Oliver J. Schmitz, Daniel W.J. Kwong, Ricky N.S. Wong, Zongwei Cai. (2008) Quantification of aristolochic acid-derived DNA adducts in rat kidney and liver by using liquid chromatography–electrospray ionization mass spectrometry. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 646:1-2, 17-24
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Frédéric D Debelle, Jean-Louis Vanherweghem, Joëlle L Nortier. (2008) Aristolochic acid nephropathy: A worldwide problem. Kidney International 74:2, 158-169
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Wan Chan, Kim-Chung Lee, Ning Liu, Ricky N. S. Wong, Huwei Liu, Zongwei Cai. (2008) Liquid chromatography/mass spectrometry for metabonomics investigation of the biochemical effects induced by aristolochic acid in rats: the use of information-dependent acquisition for biomarker identification. Rapid Communications in Mass Spectrometry 22:6, 873-880
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