IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

SOME TRADITIONAL HERBAL MEDICINES 99
Figure 6. Metabolic activation and DNA adduct formation of aristolochic acids I
(R = OCH 3) and II (R–H)
O
O
O
O
O
1
N
N
COOH
R
R
O
NO 2 O
N
N
HN
NH
4
C
O
O
O
(b) Mutations in proto-oncogenes in tumours induced by aristolochic
acids in rodents in vivo (see Table 5 for details of studies and
references)
Activated c-Ha-ras proto-oncogenes were found in 7/7 ear-duct tumours (squamouscell
carcinoma), in 13/14 forestomach tumours (squamous-cell carcinoma) and in the
transformant of the 14th forestomach tumour, and in one metastasis in the lung induced
in rats by aristolochic acid I. The mutations were all A → T transversions at the second
base of codon 61. In the same animal study, activated c-Ki-ras proto-oncogenes were
found in 1/7 ear duct tumours and 1/8 tumours of the small intestine. In the one metas-
2
O
R
C
O
N
+ DNA
O
O
N
N
O
N
NH
5
N
O
O
H
HN
From Schmeiser et al. (1997)
(1) Aristolochic acid; (2) cyclic nitrenium ion of aristolochic acids I or II; (3) aristolactams; (4) 7-(deoxyadenosin-N
6 -yl)aristolactam I or II (dA-AAI or dA-AAII); (5) 7-(deoxyguanosin-N 2 -yl)aristolactam I or II
(dG-AAI or dG-AAII)
R
C
O
3
C
R
O
O
NH
O