IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

11 rats on day 105 in the high-dose group. Urothelial dysplasia was also seen in a few
rats of the low-dose group on day 10 or 105. Three of the high-dose group developed
papillary urothelial carcinomas by day 105. Malignant fibrohistiocytic sarcomas were
found on day 105 around the sites of subcutaneous injection in two of the six rats of the
low-dose group and in seven of the 11 of the high-dose group. Marked interstitial fibrosis
of the kidney was noted in the high-dose group on day 35. None was seen in the lowdose
or controls groups (Debelle et al., 2002).
4. Other Data Relevant to an Evaluation of
Carcinogenicity and its Mechanisms
4.1 Absorption, distribution, metabolism and excretion
4.1.1 Humans
As part of a clinical study designed to investigate the effects of aristolochic acids on
the phagocytic activity of granulocytes, six healthy volunteers were given a daily dose
[presumably oral but not explicitly stated] of 0.9 mg of a mixture of aristolochic acids I
and II [ratio not specified] for several days, and 24-h urine samples from day 3 of this
trial were analysed for metabolites. The only metabolites detected were aristolactam I
(metabolite of aristolochic acid I) and aristolactam II (metabolite of aristolochic acid II)
(Figure 5). The percentage conversions to these two metabolites were not reported
(Krumbiegel et al., 1987). This contradicts an earlier report of oral absorption of aristolochic
acid in humans resulting in the compound(s) being excreted unchanged in urine,
bile, breast milk and cerebrospinal fluid (Schulz et al., 1971).
4.1.2 Experimental systems
SOME TRADITIONAL HERBAL MEDICINES 89
In an extensive study following oral administration of aristolochic acids I and II to
male Wistar rats (pure compounds given; 3 mg), the following metabolites were detected
in urine and faeces: from aristolochic acid I — aristolactam I, aristolactam Ia, aristolochic
acid Ia, aristolic acid I and 3,4-methylenedioxy-8-hydroxy-1-phenanthrenecarboxylic
acid; from aristolochic acid II — aristolactam II, aristolactam Ia and 3,4-methylenedioxy-1-phenanthrenecarboxylic
acid (Krumbiegel et al., 1987). The structures of
these compounds (Figure 5) were determined by spectroscopic methods including lowresolution
electron-impact mass spectrometry and low-field 1 H-NMR spectrometry
(100 MHz) (Krumbiegel & Roth, 1987). A further metabolite of aristolochic acid II with
a lactam moiety was not fully characterized. The principal metabolite of aristolochic
acid I in rats was aristolactam Ia (46% of the dose converted to this was found in the
urine and 37% in the faeces). In the urine, most of the aristolactam Ia was present as a
conjugated form, which required alkaline treatment (3 M NaOH) for hydrolysis. The