Global regulatory sanctions against specific natural products are rare, with nationalistic autonomy often prevailing over multi-continental sales and importation restrictions. One illustration of the former is the case built around two different aristolochic acids (AA).
AA is present in different species of the genus Aristolochia, but has also been described in certain Asarum species and in oregano leaves, albeit in relatively lesser concentrations.1,2 Classically, Aristolochia species have been used for venomous snakebites and in obstetrics as an abortifacient. Pharmacological research appears to confirm both actions when administered via injection but not after oral ingestion.3,4
The investigation that initiated the toxic potential of AA in humans was a 1993 series of kidney failure cases at a Belgian weight-loss clinic.5 In 1990 this clinic began prescribing a reformulated, encapsulated Chinese herbal preparation intended to contain, in part, Stephania tetrandra (for its purported diuretic effects; 100-200mg/day total dose) accompanied by a regimen of other agents. After an exceptionally high incidence of varying degrees of kidney failure was noted among nine women, phytochemical evaluation of the Chinese herbal product appeared to confirm the absence of S. tetrandra. The authors noted the similarity in the species name of Aristolochia fangchi with the Chinese name for S. tetrandra, fang ji. Follow-up investigations by the same research team identified another 41 women, 18 of whom required kidney transplants.
What is enigmatic about this report is the apparent absence of any known plant kidney toxins, based upon the absence of AA via thin layer chromatographic evaluation. However, subsequent to this paper being published, Chinese researchers identified A. fangchi in a Chinese herb sample shipped to Belgium bearing the name S. tetrandra (fang ji).6 AA was later detected in the Belgian imports of S. tetrandra when more robust analytical tools were utilized,7 suggesting that the apparent absence of AA in the 1993 paper was due to analytical challenges.
Much preclinical and clinical research ensued after the 1993 paper. Most notable is the diagnosis of cancer of the urinary tract among a high proportion of users (with prior severe kidney failure) of a Chinese herbal product inadvertently labelled to contain S. tetrandra but actually containing A. fangchi.8 Convincingly, metabolites of AA bound to DNA from the kidneys of patients that were surgically removed prior to transplant replacement were identified.10 A more recent case report suggests that urinary tract cancer can manifest in the absence of kidney failure.11 Analysis of S. tetrandra has confirmed the absence of AA,12 while a recent clinical case report has confirmed the presence of a specific DNA mutation in the urinary tract associated with DNA-AA adducts and cancer.13
Japan, Switzerland, Canada, Belgium and Germany have banned Aristolochia species imports and the sale of products containing this plant, while the US Food and Drug Administration has issued an import alert. Despite this latter action, there appear to be a number of products containing Aristolochia species offered for sale through US websites.14
Collectively, these findings compose a sharp contrast to the relative paucity of experimental and systematic clinical evidence that was marshalled to support the ban of dietary supplements containing ephedrine and related alkaloids in the US.
Anthony Almada, MSc, is president and chief scientific officer of IMAGINutrition Inc.
All correspondence will be forwarded to the author.
References1. Jong TT, et al. Analysis of aristolochic acids in nine sources of Xixin, a traditional Chinese medicine, by liquid chromatography/atmospheric pressure chemical ionisation/tandem mass spectrometry. J Pharm Biomed Anal 2003; 33:831-7.
2. Goun E, et al. Antithrombin activity of some constituents from Origanum vulgare. Fitoterapia 2002; 73:692-4.
3. Marshall LA, et al. Preliminary studies on phospholipase A2-induced mouse paw edema as a model to evaluate anti-inflammatory agents. J Cell Biochem 1989; 40:147-55.
4. Ganguly T, et al. Disruption of pregnancy in mouse by aristolocic acid: I. Plausible explanation in relation to early events. Contraception 1986; 34:625-37.
5. Vanherweghem JL, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341:387-91.
6. But PP. Need for correct identification of herbs in herbal poisoning [Letter]. Lancet 1993; 341:637.
7. Vanhaelen M, et al. Identification of aristolochic acid in Chinese herbs [Letter]. Lancet 1994; 343:174.
8. Cosyns JP, Aristolochic acid and ?Chinese herbs nephropathy.? Drug Safety 2003; 26:233-48.
9. Cosyns JP, et al. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999; 33:1011-7.
10. Nortier JL, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000; 342:1686-92.
11. Nortier JL, et al. Invasive urothelial carcinoma after exposure to Chinese herbal medicine containing aristolochic acid may occur without severe renal failure. Nephrol Dial Transplant 2003; 18:426-8.
12. Sun Z, et al. An easy and rapid method to determine aristolochic acids I and II with high sensitivity. Anal Biochem Chem 2004; 378:388-90.
13. Lord GM, et al. DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy. Am J Kidney Dis 2004; 43:e11-7.
14. Gold LS and Slone TH. Aristolochic acid, an herbal carcinogen, sold on the web after FDA alert [Lett]. N Engl J Med 2003; 349:1576-7.