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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceuticals. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100A.)

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PLANTS CONTAINING ARISTOLOCHIC ACID

Plants containing aristolochic acid were considered by a previous IARC Working Group in 2002 (IARC, 2002). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation.

1. Exposure Data

For the purpose of this Monograph, unless otherwise specified, the term ‘aristolochic acids’ refers to an extract of Aristolochia species comprising a mixture of aristolochic acid I and its demethoxylated derivative, aristolochic acid II. Aristolochia species also contain the related aristolactams, which are phenanthrene cyclic amides (EMEA, 2000). In some of the older literature, it is unclear whether individual compounds or mixtures are being discussed when referring to ‘aristolochic acid’.

1.1. Identification of the agent

Aristolochia species refers to several members of the genus (family Aristolochiaceae) (WHO, 1997) that are often found in traditional Chinese medicines, e.g. Aristolochia debilis, A. contorta, A. manshuriensis, and A. fangchi. The medicinal parts of each plant (i.e., stem, root, fruit) have distinct Chinese names. Details on these traditional drugs can be found in the Pharmacopoeia of the People’s Republic of China (Commission of the Ministry of Public Health, 2000), except where noted. This Pharmacopoeia includes the Aristolochia species presented in Table 1.1.

Table 1.1. Aristolochia species included in the Pharmacopoeia of the People’s Republic of China.

Table 1.1

Aristolochia species included in the Pharmacopoeia of the People’s Republic of China.

In traditional Chinese medicine, Aristolochia species are also considered to be interchangeable with other commonly used herbal ingredients, and substitution of one plant species for another is established practice. Herbal ingredients are traded using their common Chinese Pin Yin name, and this can lead to confusion. For example, the name ‘Fang Ji’ can be used to describe the roots of Aristolochia fangchi, Stephania tetrandra, or Cocculus species (EMEA, 2000).

Similarly, the name ‘Mu Tong’ is used to describe Aristolochia manshuriensis, and certain Clematis or Akebia species. In some reports in the Chinese literature, ‘Mu Tong’ is substituted with ‘Ma Dou Ling’ (EMEA, 2000).

Table 1.2 lists botanicals known or suspected to contain aristolochic acid.

Table 1.2. Botanicals known or suspected to contain aristolochic acid.

Table 1.2

Botanicals known or suspected to contain aristolochic acid.

1.1.1. Aristolochic acid I

  • Chem. Abstr. Serv. Reg. No.: 313-67-7
  • Chem. Abstr. Serv. Name: 8-Methoxy-6-nitrophenanthro[3,4-d]-1,3-dioxole-5-carboxylic acid
  • IUPAC Systematic Name: 8-Methoxy-6-nitronaphtho[2,1-g][1,3]benzodioxole-5-carboxylic acid
  • Synonyms: Aristinic acid; aristolochia yellow; aristolochic acid A; aristolochin; aristolochine; Descresept; isoaristolochic acid; 8-methoxy-3,4-methylenedioxy-10-nitrophenanthrene-1-carboxylic acid; 3,4-methylenedioxy-8-methoxy-10-nitro-1-phenanthrenecarboxylic acid
  • Description: Shiny brown leaflets (O’Neil, 2006)
(a) Structural and molecular formulae, and relative molecular mass

Image 978-9283213185-C023-F001.jpg

C17H11NO7

Relative molecular mass: 341.27

1.1.2. Aristolochic acid II

  • Chem. Abstr. Serv. Reg. No.: 475-80-9
  • Chem. Abstr. Serv. Name: 6-Nitrophenanthro[3,4-d]-1,3-dioxole-5-carboxylic acid
  • IUPAC Systematic Name: 6-Nitronaphtho[2,1-g][1,3]benzodioxole-5-carboxylic acid
  • Synonyms: Aristolochic acid B; 3,4-methylenedioxy-10-nitrophenanthrene-1-carboxylic acid
(a) Structural and molecular formula, and relative molecular mass

Image 978-9283213185-C023-F002.jpg

C16H9NO6

Relative molecular mass: 311.25

1.2. Use of the agent

Several Aristolochia species (notably A. contorta, A. debilis, A. fangchi, and A. manshuriensis) have been used in traditional Chinese medicine as anti-inflammatory agents, diuretics, and in the treatment of oedema (IARC, 2002). In addition, Chinese herbal remedies labelled ‘Fang Ji’ were sold in Europe as slimming agents. The ingredient S. tetrandra was substituted with A. fangchi in the preparation distributed in Belgium during the period 1990–92 (Nortier et al., 2000).

The aristolochic acid occurring in Aristolochia species used in traditional herbal medicines has been reported to function as a phospholipase A2 inhibitor, and as an antineoplastic, antiseptic, anti-inflammatory, and bactericidal agent (Buckingham, 2001; Cosyns, 2003).

2. Cancer in Humans

The previous evaluation of herbal remedies containing plant species of the genus Aristolochia was based on four case reports and two ecological studies (IARC, 2002). These studies as well as more recent publications are presented below.

2.1. Case reports

Since the early 1990s, several case reports from various countries have raised the possibility of a link between the consumption of Chinese herbal products containing Aristolochia species and human nephropathy (Chinese herb nephropathy, subsequently called aristolochic acid nephropathy), and urothelial cancer (Cosyns et al., 1994; Vanherweghem et al., 1995; Yang et al., 2000; Lord et al., 2001, 2004; Arlt et al., 2004).

2.2. Aristolochic acid nephropathy

Cosyns et al. (1999) examined 19 kidneys and ureters removed prophylactically during and/or after renal transplantation from ten patients treated for aristolochic acid nephropathy in one urology unit in Belgium. [The Working Group noted that no further specification of the formulation of the herbs was given.] The patients were all women with a mean age of 40 years (range 27–59 years). Multifocal high-grade carcinoma in situ was observed in four patients (40%).

Nortier et al. (2000) examined 77 kidneys and 78 ureters removed prophylactically from 39 patients treated for aristolochic acid nephropathy in another urology unit in Belgium. The period of use among these patients was closely related to the period of distribution in Belgium of pills containing A. fangchi (from 1990–92). Except for a 60-year-old man, all patients were women (aged 54 ± 7 years). Eighteen cases of urothelial carcinoma were found (prevalence, 46%; 95%CI, 29–62%). Except for one case of bladder cancer, all the carcinomas were located in the upper urinary tract and were almost equally distributed between the pelvis and the ureter. Mild-to-moderate dysplasia of the urothelium was found in 19 of the 21 patients without urothelial carcinoma. Among 24 patients who reported a cumulative consumption of less than 200 g of herbs containing A. fangchi, eight cases of urothelial cancer were recorded, and among the 15 patients who had ingested more than 200 g, ten cases of urothelial cancer were observed (P = 0.05).

[The Working Group noted that there were no control groups in either studies for nephropathy or cancer; however, the use of Chinese herbs by all women, the absence of other common exposure, the presumed low prevalence of malignant disease in this age group compared to the high prevalence observed, and the strong temporal association led the Working Group to the conclusion that there is a causal association between use of the herb and nephropathy/urothelial cancer.]

3. Cancer in Experimental Animals

3.1. Aristolochic acid

Aristolochic acid, tested for carcinogenicity mainly by oral administration in several studies in rats, one study in mice, and by intraperitoneal injection in one study in rabbits, induced tumours at multiple sites. In most studies, the animals were administered a mixture of aristolochic acid I and II (see Table 3.1). However, carcinogenic effects were also observed with aristolochic acid I alone (Schmeiser et al., 1990; Cui et al., 2005).

Table 3.1. Studies of cancer in experimental animals exposed to aristolochic acid.

Table 3.1

Studies of cancer in experimental animals exposed to aristolochic acid.

In female NMRI mice, a mixture of aristolochic acid I and II given orally at a dose of 5 mg/kg body weight for 3 weeks increased the incidence of forestomach tumours, kidney adenomas, and lung carcinomas (Mengs, 1988).

Oral administration of aristolochic acid to rats caused a dose- and time-dependent tumour response. Exposure to 50 mg/kg body weight aristolochic acid I for 3 days resulted in neoplastic lesions of the kidney after 6 months (Cui et al., 2005). Rats exposed to lower doses by gavage over a longer period (1–10 mg/kg body weight for 3–6 months or 0.1 mg/kg body weight for 12 months) developed a variety of benign or malignant tumours, including those of the forestomach, kidney, renal pelvis, urinary bladder, ear duct, thymus, small intestine, and pancreas. Single cases of haematopoietic system, lung, mammary gland, and peritoneal tumours were also reported (Mengs et al., 1982; Mengs, 1983; Schmeiser et al., 1990; Hadjiolov et al., 1993; Cosyns et al., 1998).

Subcutaneous injection of 10 mg/kg body weight aristolochic acid into rats for 35 days induced a low incidence of urothelial carcinomas and fibrohistiocytic sarcomas at the injection site (Debelle et al., 2002). A single intraperitoneal injection of aristolochic acid at 10 mg/kg body weight increased the incidence of liver neoplastic nodules in male F344 rats when coupled with the liver tumour promoter orotic acid (Rossiello et al., 1993).

Rabbits given intraperitoneal injections of aristolochic acid at 0.1 mg/kg body weight for 17–21 months developed tumours of the kidney, ureter, and of the peritoneal cavity (Cosyns et al., 2001).

3.2. Extracts from Aristolochia species

Decoctions from A. manshuriensis and an aqueous extract of A. fructus, when administered orally to rats, induced tumours of the forestomach and the kidney (Qiu et al., 2000; Hwang et al., 2006).

See Table 3.2

Table 3.2. Studies of cancer in experimental animals exposed to extracts from Aristolochia species.

Table 3.2

Studies of cancer in experimental animals exposed to extracts from Aristolochia species.

3.3. Herbal remedy containing aristolochic acids

Squamous cell carcinomas of the forestomach were found in male rats treated with a weight-loss regimen of herbal ingredients that contained aristolochic acids (Cosyns et al., 1998).

See Table 3.3

Table 3.3. Studies of cancer in experimental animals exposed to a herbal weight-loss regimen containing aristolochic acid.

Table 3.3

Studies of cancer in experimental animals exposed to a herbal weight-loss regimen containing aristolochic acid.

4. Other Relevant Data

4.1. Absorption, distribution, metabolism, and excretion

Aristolochic acid is absorbed from the gastrointestinal tract and distributed unchanged and/or in metabolized form throughout the body. Several structurally defined metabolites (mainly nitroreduction products) were identified following the oral administration of aristolochic acid I and aristolochic acid II to rats and mice (Krumbiegel et al., 1987; Chan et al. 2006, 2007). Fewer metabolites were observed in beagle dogs, rabbits, guinea-pigs, and humans than in rats or mice (Krumbiegel et al., 1987). The major metabolites of aristolochic acid are products derived from nitroreduction, O-demethylation, and denitration. In humans, the reduction products aristolactam I and II are the only metabolites detected in urine (Krumbiegel et al., 1987), although full metabolic profiles have not been reported. Phase II metabolites of aristolochic acids have been identified in the urine of rats, and include N- and O-glucuronides, and acetate and sulfate esters (Chan et al., 2007).

4.2. Toxic effects

The toxic effects of aristolochic acids I and II have been inferred from effects seen in patients diagnosed with kidney nephropathy as a result of consuming herbal mixtures containing Aristolochia species, leading to rapidly progressive fibrosing interstitial nephritis (Nortier et al., 2000). 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 (IARC, 2002; Cosyns, 2003).

4.3. Genotoxic effects

Aristolochic acids are consistently active in genotoxicity tests in vivo and in vitro (Arlt et al., 2002a; IARC, 2002). The major activation pathway involves reduction of the nitrogroup, and is catalysed by several human cytosolic and microsomal enzymes such as hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase (NQO1), hepatic microsomal cytochrome P450 (CYP)1A2 and renal microsomal NADPH:CYP reductase – NQO1 being the most important (Stiborová et al., 2008). During reductive activation, aristolochic acids form an electrophilic cyclic N-acylnitrenium ion that reacts with purine bases to form DNA adducts. These aristolochic-acid-specific DNA adducts have been identified and detected in experimental animals exposed to aristolochic acid or botanical products containing aristolochic acid, and in urothelial tissues from aristolochic acid nephropathy patients (Arlt et al., 2002a, b). In addition, Grollman et al. (2007) detected DNA adducts derived from aristolochic acids in formalin-fixed renal cortical tissues embedded in paraffin blocks from four patients with a verified Balkan endemic nephropathy and in tumour tissue from three long-term residents of endemic villages who had upper urinary tract cancer. No such adducts were detected in five control patients with common forms of chronic renal disease or in five control patients with upper urinary tract transitional cell cancers who resided in a non-endemic region in Croatia. In rodent tumours, the major DNA adduct formed by aristolochic acid (7-[deoxyadenosin-N6-yl]aristolactam I) has been associated with the activation of RAS oncogenes through a specific CAA→CTA transversion mutation in codon 61 (Schmeiser et al., 1990; Cheng et al., 2006). Such A:T→T:A transversions were the predominant mutation type in studies using transgenic MutaTMmice (Kohara et al., 2002), Big Blue transgenic rats (Chen et al., 2006; Mei et al., 2006), and in human TP53 knock-in mouse fibroblasts treated with aristolochic acid (Liu et al., 2004; Feldmeyer et al., 2006). In humans, A:T→T:A transversion mutations in codon 139 of exon 5 of the TP53 gene were identified in an urothelial tumour from an aristolochic acid nephropathy patient (Lord et al., 2004), and in several patients having Balkan endemic nephropathy, along with aristolochic-acid-specific DNA adducts (Lord et al., 2004; Grollman & Jelaković, 2007; Grollman et al., 2007).

4.4. Synthesis

Key steps in the mechanism by which aristolochic acid causes tumours in experimental animals have been identified (Arlt et al. 2002a), and are consistent with events occurring in patients with urothelial cancers associated with aristolochic acid nephropathy and Balkan endemic nephropathy. The same DNA adducts identified in humans are also found in experimental animals (Arlt et al. 2002a, b) exposed to the natural mixture or the pure major components. A:T→T:A transversions in the TP53 gene in urothelial tumours of aristolochic acid nephropathy and Balkan endemic nephropathy patients were the predominant mutations found in human TP53 knock-in mouse fibroblasts treated with aristolochic acid (Liu et al., 2004; Feldmeyer et al., 2006; Arlt et al., 2007). Collectively, these data support the strong mechanistic evidence of the carcinogenicity of aristolochic acid – a mixture of aristolochic acids I and II – in humans.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of plants containing aristolochic acid. Plants containing aristolochic acid cause cancer of the renal pelvis, and of the ureter.

There is sufficient evidence in experimental animals for the carcinogenicity of extracts of plants containing aristolochic acid.

There is limited evidence in humans for the carcinogenicity of aristolochic acid.

There is sufficient evidence in experimental animals for the carcinogenicity of aristolochic acid.

Plants containing aristolochic acid are carcinogenic to humans (Group 1).

Aristolochic acid is carcinogenic to humans (Group 1).

In making the overall evaluation of aristolochic acid, the Working Group took into consideration that:

• Aristolochic-acid-specific DNA adducts identified in experimental animals exposed to aristolochic acid or herbal products containing aristolochic acid were found in urothelial tissue of aristolochic acid nephropathy patients, in renal tissue from Balkan endemic nephropathy patients, and in tumour tissue from residents of endemic villages.

• A:T→T:A transversions were found in the TP53 gene of urothelial tumours from aristolochic acid nephropathy patients and Balkan endemic nephropathy patients. The same type of mutation predominated in human TP53 knock-in mouse fibroblasts treated with aristolochic acid.

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© International Agency for Research on Cancer, 2012. For more information contact publications@iarc.fr.
Bookshelf ID: NBK304331

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