Vol. 9, No 1, 2002 pp. 53 - 56
UC 616.61-004
ARISTOLOCHIC ACID AS A RISK FACTOR
FOR BALKAN ENDEMIC NEPHROPATHY
Heinz H. Schmeiser1, Volker M. Arlt2,
Dusan Ferluga3, Marie Stiborova4,
Annie Pfohl-Leszkowicz5,
Mato Vukelic6, Stjepan Ceovic6,
Jean-Pierre Cosyns7
1Division of Molecular Toxicology,
German Cancer Research Center, Heidelberg, Germany
2Section of Molecular Carcinogenesis,
Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK
3Institute of Pathology, University
of Ljubljana, Ljubljana, Slovenia
4Department of Biochemistry, Charles
University, Prague, The Czech Republic
5Ecole Nationale Supérieure Agronomique
de Toulouse, Laboratoire de Toxicologie et Sécurité Alimentaire, Auzeville
Tolosane, France
6Department of Pathology, General Hospital
"Dr. J. Bencevic", Slavonski Brod, Croatia
7Department of Pathology, Université
Catholique de Louvain, Medical School, Brussels, Belgium
E-mail: h.schmeiser@dkfz.de
Summary. Background/Aims: Aristolochic acid nephropathy (AAN) is
a unique type of rapidly progressive interstitial fibrosis, associated
with urothelial cancer and related to the prolonged intake of Chinese herbal
remedies (Aristolochia species) containing nephrotoxic and carcinogenic
aristolochic acid (AA). On both clinical and morphological grounds, AAN
is very similar to another fibrosing nephropathy, the Balkan endemic nephropathy
(BEN), including the association with urothelial tumours. It has been suggested
that the mycotoxin ochratoxin A (OTA) is associated with BEN, but also
AA was considered as a possible causal factor in BEN already in the 1970s.
Methods: We assessed AA exposure in endemic areas for BEN using the
32P-postlabelling method. To this end we analysed renal tissue from three
female farmers who lived in endemic areas and in two of whom an upper urinary
tract cancer had developed, for OTA-related and AA-DNA adducts, described
biomarkers of exposure for both genotoxins.
Results: In two of the three cases of whom one had urothelial malignancy,
the major adenosine adduct of aristolochic acid I, 7-(deoxyadenosin-N6-yl)-aristolactam
I (dA-AAI), the most abundant AA-DNA adduct found in AAN patients, was
identified by cochromatographic analyses on TLC and HPLC. In the same two
patients OTA-related DNA adducts were detected. In the third patient, the
tentatively assigned dA-AAI-DNA adduct spot was very faint and precluded
complete identification. OTA-related DNA adducts were absent. Our data
confirm the potential role of OTA in the development of urinary tract tumours
in endemic regions and clearly demonstrate that people living in endemic
areas for BEN have been exposed to AA, too.
Conclusions: Thus, AA should be considered as an additional potential
risk factor. The epidemiology of AAN and AAN-associated urothelial malignancies
might provide a clue to urothelial malignancies in endemic areas. Whether
AA plays a role also in BEN remains to be further assessed in patients
with definite diagnosis of BEN and in patients with other nephropathies
but living in endemic areas for BEN.
Key words: Balkan endemic nephropathy, DNA adducts, aristolochic
acid, 32P-postlabeling
