IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

96
4.4 Genetic and related effects
4.4.1 Humans
(a) DNA-adduct formation in patients with Chinese herb nephropathy
(see Table 3 for details of studies and references)
Aristolochic acid-specific DNA adducts have been detected by the 32P-postlabelling method in the kidneys and ureters of patients with Chinese herb nephropathy (a total of
47 women and one man). The major DNA adduct, which co-chromatographed with
7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI), was detected in all urothelial tissues
analysed, whereas the two minor ones, chromatographically indistinguishable from
7-(deoxyguanosin-N2-yl)aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristo lactam II (dA-AAII), were found in most cases (see Figure 6). Total aristolochic acidspecific
adduct levels in DNA obtained from whole organs or biopsies from Chinese herb
nephropathy patients were in the range of 1.7–530 adducts per 109 normal nucleotides.
All studies presented evidence that these patients had taken herbal preparations containing
a natural mixture of aristolochic acids.
(b) p53 overexpression in patients with Chinese herb nephropathy
Overexpression of the p53 protein, a common finding in human tumours, was
observed in carcinoma in situ, papillary transitional-cell carcinoma and urothelial atypia
found in 10 Belgian patients with Chinese herb nephropathy (Cosyns et al., 1999).
4.4.2 Experimental systems
IARC MONOGRAPHS VOLUME 82
(a) DNA adduct formation by aristolochic acids in rats in vivo (see
Table 4 for details of studies and references)
Aristolochic acid–DNA adducts were formed in vivo in many organs of male rats
given oral doses of aristolochic acid (natural mixture) or the pure major components
aristolochic acid I or aristolochic acid II. Aristolochic acid–DNA adducts were also
formed in vivo in the kidney (the only organ examined) of male and female rats given
multiple oral doses of a slimming regimen of plant material that contained aristolochic
acids. The results confirm that the three major DNA adducts formed in vivo co-chromatograph
with 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI), 7-(deoxyguanosin-N2-yl) aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristolactam II (dA-AAII). Oral
administration of a single dose of aristolochic acid I to rats led to formation of the dA-
AAI adduct that persisted in DNA of several organs, consistent with the results obtained
from studies in patients with Chinese herb nephropathy.