The old herbal drug aristolochic acid (AA), derived from Aristolochia spp., has been
associated with the development of a novel nephropathy, designated aristolochic acid
nephropathy (AAN), and urothelial cancer in AAN patients. There is clear evidence
that the major components of the plant extract AA, aristolochic acid I (AAI) and aristolochic
acid II (AAII), both nitrophenanthrene carboxylic acids, are genotoxic mutagens forming
DNA adducts after metabolic activation through simple reduction of the nitro group.
Several mammalian enzymes have been shown to be capable of activating both AAI and
AAII in vitro and in cells. The activating metabolism has been elucidated and is consistent
with the formation of a cyclic nitrenium ion with delocalized charge leading to the
preferential formation of purine adducts bound to the exocyclic amino groups of deoxyadenosine
and deoxyguanosine. The predominant DNA adduct in vivo, 7-(deoxyadenosin-N(6)-yl)aristolactam
I (dA-AAI), which is the most persistent of the adducts in target tissue, is a mutagenic
lesion leading to AT-->TA transversions in vitro. This transversion mutation is found
at high frequency in codon 61 of the H-ras oncogene in tumours of rodents induced
by AAI, suggesting that dA-AAI might be the critical lesion in the carcinogenic process
in rodents. DNA-binding studies confirmed that both AAs bind to the adenines of codon
61 in the H-ras mouse gene and preferentially to purines in the human p53 gene. In
contrast, the molecular mechanism of renal interstitial fibrosis in humans after chronic
administration of AA remains to be explored. However, preliminary findings suggest
that DNA damage by AA is not only responsible for the tumour development but also
for the destructive fibrotic process in the kidney. It is concluded that there is
significant evidence that AA is a powerful nephrotoxic and carcinogenic substance
with an extremely short latency period, not only in animals but also in humans. In
particular, the highly similar metabolic pathway of activation and resultant DNA adducts
of AA allows the extrapolation of carcinogenesis data from laboratory animals to the
human situation. Therefore, all products containing botanicals known to or suspected
of containing AA should be banned from the market world wide.