Carcinogenesis, Vol 18, 1063-1067, Copyright © 1997 by Oxford University Press
CA Bieler, M Stiborova, M Wiessler, JP Cosyns, C van Ypersele de Strihou and HH Schmeiser
Recently, we reported that aristolochic acid (AA) a naturally occurring
nephrotoxin and carcinogen is implicated in a unique type of renal
fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified
the principal aristolochic acid-DNA adduct in the kidney of five such
patients. We now extend these observations and demonstrate the presence of
additional AA-DNA adducts by the 32P-post-labelling method not only in the
kidneys, but also in a ureter obtained after renal transplantation. Using
the nuclease P1 version of the assay not only the major DNA adduct of
aristolochic acid, 7-(deoxyadenosin-N6-yl)- aristolactam I (dA-AAI), but
also the minor adducts, 7-(deoxyguanosin- N2-yl)-aristolactam I (dG-AAI)
and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and
identified by cochromatographic analyses with TLC and HPLC. Quantitative
analyses of six kidneys revealed relative adduct levels from 0.7 to
5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/
10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is
consistent with the occurrence of aristolochic acid II (AAII) in the herb
powder imported under the name of Stephania tetrandra and confirms that the
patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-
labelling analyses of further biopsy samples of one patient showed the
known adduct pattern of AA exposure not only in the kidney, but also in the
ureter, whereas in skin and muscle tissue no adduct spots were detectable.
In an attempt to explain the higher level of the dA-AAI adduct compared to
the dG-AAI adduct level in renal tissue even 44 months after the end of
regimen, the persistence of these two purine adducts was investigated in
the kidney of rats given a single oral dose of pure AAI. In contrast to the
dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the
kidney of rats. Our data demonstrate that AA forms DNA adducts in human
tissue by the same activation mechanism(s) reported from animal studies.
Thus, the carcinogenic/mutagenic activity of AA observed in animals could
also be responsible for the urothelial cancers observed in two of the CHN
patients.
ARTICLES
32P-post-labelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy
Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.
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