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varied from undetectable (< 0.02 mg/g) to 1.56 mg/g (mean ± SD, 0.66 ± 0.56 mg/g)
(Vanhaelen et al., 1994).
Further evidence supports the involvement of aristolochic acids I and II in the kidney
disease: 7-(deoxyadenosin-N 6 -yl)aristolactam I–DNA adduct (dA-AAI) was detected in
renal tissue obtained from five patients with Chinese herb nephropathy, while none was
found in renal tissue from six patients with other renal diseases (Schmeiser et al., 1996;
see Section 4.4.1). A larger series of kidney samples from 38 patients with Chinese herb
nephropathy confirmed the presence of DNA adducts formed by aristolochic acid six
years after their exposure to the so-called Stephania tetrandra powder (actually, Aristolochia
fangchi). Such adducts were absent in kidney tissues obtained from eight patients
with renal disease of other origin (Nortier et al., 2000; see Section 4.4.1).
After the description of the initial cases (Vanherweghem et al., 1993), similar cases
of Chinese herb nephropathy were reported in many other countries: four cases in France
secondary to the intake of slimming pills containing Stephania tetrandra which was, in
fact, Aristolochia fangchi (Pourrat et al., 1994; Stengel & Jones, 1998); one case in Spain
after chronic intake of a tea made with a mixture of herbs containing Aristolochia
pistolochia, a herb that was grown in the Catalonia region (Peña et al., 1996); two cases
in the United Kingdom after treatment of eczema with Mu Tong containing aristolochic
acid (Lord et al., 1999); 12 cases in Taiwan related to the use of various unidentified
herbal medications for different purposes (Yang et al., 2000); one case in the USA after
intake of herbal medicine containing aristolochic acid for low back pain (Meyer et al.,
2000); and 12 cases in Japan, in five of which the presence of aristolochic acid was
demonstrated in the herbal medicine; in the other cases, confusion of Mokutsu (Akebia
quinata) with Kan-Mokutsu (Aristolochia manshuriensis) and Boui (Sinomenium
acutum) with Kou-Boui (Aristolochia fangchi) or Kanchu-Boui (Aristolochia heterophylla)
was suspected (Tanaka et al., 2001). In Japan, the cases of Chinese herb nephropathy
often presented with adult-onset Fanconi syndrome (Tanaka et al., 2000a,b). A
similar case was reported in Germany after intake of a purported Akebia preparation
containing aristolochic acid (Krumme et al., 2001).
4.2.2 Experimental systems
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In a study of acute effects of a mixture of aristolochic acids I (77.2%) and II (21.2%),
intragastric or intravenous administration at high doses to male and female mice (NMRI)
and rats (Wistar) resulted in death from acute renal failure within 15 days. The oral LD 50
ranged from 56 to 203 mg/kg bw and the intravenous LD 50 from 38 to 83 mg/kg bw,
depending on the species and sex. The predominant histological features were severe
necrosis of the renal tubules, atrophy of the spleen and thymus, superficial ulceration of
the forestomach by both routes, followed by hyperplasia and hyperkeratosis of the
squamous epithelium (Mengs, 1987).
In a follow-up study, a no-effect level of 0.2 mg/kg bw — given daily by gavage for
four weeks — was observed for aristolochic acids in male Wistar rats. Mild changes only