ARISTOLOCHIA SPECIES AND ARISTOLOCHIC ACIDS
HERBAL REMEDIES CONTAINING PLANT SPECIES
OF THE GENUS ARISTOLOCHIA (Group 1)
NATURALLY OCCURRING MIXTURES OF
ARISTOLOCHIC ACIDS (Group 2A)
For definition of Groups, see Preamble Evaluation.
VOL.: 82 (2002) (p. 69)
Aristolochic acid I
Aristolochic acid II
5. Summary of Data Reported and Evaluation
5.1 Exposure data
Several Aristolochia species (notably A. contorta, A. debilis, A. fangchi and A. manshuriensis) have been used in traditional Chinese medicine as anti-rheumatics, as diuretics and in the treatment of oedema. Aristolochic acids are nitrophenanthrene carboxylic acid derivatives that are constituents of these plant species.
5.2 Human carcinogenicity data
An outbreak of rapidly progressive renal fibrosis in Belgium involved at least 100 patients, mostly middle-aged women undergoing a weight-loss regimen that included use of a mixture of Chinese herbs containing Aristolochia species incorrectly labelled as Stephania tetrandra. Additional cases of rapidly progressive renal disease involving Chinese herbs have been reported from at least five other countries in Europe and Asia. This syndrome has been called ‘Chinese herb nephropathy’.
Because of a few early cases of urothelial cancer among Belgian patients suffering from Chinese herb nephropathy, individuals with end-stage renal disease were offered prophylactic nephroureterectomy. This surgical procedure led to the identification of a high prevalence of pre-invasive and invasive neoplastic lesions of the renal pelvis, the ureter and the urinary bladder in patients with Chinese herb nephropathy. The number of malignancies detected (18 cancers in 39 women undergoing prophylactic nephroureterectomy) greatly exceeded the expected number of these uncommon tumours. There was a positive dose–response relationship between the consumption of the herbal mixture and the prevalence of the tumours. Some cases of clinically invasive disease have been described in the follow-up of end-stage Chinese herb nephropathy patients not undergoing prophylactic nephroureterectomy.
Subsequent phytochemical investigation led to the identification of aristolochic acids in the herbal mixture consumed by these patients. While there was batch-to-batch variation in the chemical composition of such mixtures employed in the weight-loss clinics in Belgium, specific aristolochic acid–DNA adducts were found in urothelial tissue specimens from all the urothelial cancer patients, providing conclusive evidence of exposure to plants of the genus Aristolochia.
One additional case of urothelial cancer following treatment for eczema with another herbal mixture that contained aristolochic acid has been reported.
5.3 Animal carcinogenicity data
Aristolochic acids, when tested for carcinogenicity by oral administration in mice and rats and by intraperitoneal injection in rabbits, induced forestomach carcinomas in mice and rats, and fibrotic changes in the kidney together with a low incidence of kidney tumours in rabbits.
Subcutaneous injection of aristolochic acids into rats induced a low incidence of urothelial carcinomas in the kidney and malignant fibrohistiocytic sarcomas at the injection site.
5.4 Other relevant data
Several structurally defined metabolites (mainly nitroreduction products) have been reported following oral administration of aristolochic acid I (five metabolites) and aristolochic acid II (three metabolites) to rats and mice. Fewer metabolites were observed in beagle dogs, rabbits, guinea-pigs and humans than in rats and mice.
The toxic effects of aristolochic acids I and II have been inferred from effects seen in patients suffering from kidney nephropathy as a result of consuming herbal mixtures containing Aristolochia species, which leads to rapidly progressive fibrosing interstitial nephritis. In experimental animals, high doses of aristolochic acids administered either orally or intravenously caused severe necrosis of the renal tubules, atrophy of the spleen and thymus, and ulceration of the forestomach, followed by hyperplasia and hyperkeratosis of the squamous epithelium.
Various constituents of Aristolochia indica including aristolochic acids and aristolic acid (a metabolite) caused termination of pregnancy in female mice, hamsters and rabbits, but not rats. The dose levels used, however, may also lead to general toxicity.
Aristolochic acids, when metabolically activated by nitroreduction, are consistently active in genotoxicity tests in vivo and in vitro. They form DNA adducts in rodent tissues and activate ras oncogenes through a specific transversion mutation in codon 61. Aristolochic acid-specific DNA adducts were identified in urothelial tissues of all patients with Chinese herb nephropathy.
There is sufficient evidence in humans for the carcinogenicity of herbal remedies containing plant species of the genus Aristolochia.
There are no data in experimental animals on the carcinogenicity of herbal remedies containing plant species of the genus Aristolochia.
There is limited evidence in humans for the carcinogenicity of naturally occurring mixtures of aristolochic acids.
There is sufficient evidence in experimental animals for the carcinogenicity of aristolochic acids.
Herbal remedies containing plant species of the genus Aristolochia are carcinogenic to humans (Group 1).
Naturally occurring mixtures of aristolochic acids are probably carcinogenic to humans (Group 2A).
For definition of the italicized terms, see Preamble Evaluation.
SynonymsAristolochic acid I
Aristolochic acid II
See Also: Toxicological Abbreviations