XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Posters
108.
cytochrOMES P450 1A1/2 OXIDIZE carCINOGENIC arISTOLOCHIC
aCID I forMING ITS DETOXICaTION METaBOLITE aND DECreaSING
LEvELS of aa-DNA aDDUCTS IN vivo
Kateřina Levová 1 , Jana Šístková 1 , Eva Frei 2 , Volker M. Arlt 3 , David H. Phillips 3 ,
Heinz H. Schmeiser 2 and Marie Stiborová 1
1
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030,
128 40 Prague 2, Czech Republic; 2 German Cancer Research Center, 69 120 Heidelberg,
Germany; 3 Institute of Cancer Research, Section of Molecular Carcinogenesis, Sutton,
Surrey, SM2 5NG, United Kingdom
Aristolochic acid (AA) causes the development of aristolochic acid nephropathy (AAN),
the Balkan endemic nephropathy (BEN) and urothelial cancer. One of the common
features of AAN and BEN is that not all individuals exposed to AA suffer from these diseases.
We found that hepatic microsomes of wild-type (WT) mice oxidize AAI in vitro to
detoxication metabolite, AAIa, while those of a HRN line were without this effect. Levels
of AA-DNA adducts in organs of WT mice exposed to AAI were up to more than 10-fold
lower than in those of HRN mice. To define the role of CYP enzymes in AAI oxidation, we
used besides hepatic microsomes of these mouse models, also those of human and rat.
Using correlations between the CYP catalytic activities provided with the set of human
hepatic microsomes from 14 different human donors and the rates of formation of AAIa
metabolite in the same set of human hepatic microsomes, we found a highly significant
correlation coefficient between the rates of phenacetin O-deethylase, a marker for
CYP1A2, and the levels of AAIa. The results demonstrate a major role of hepatic CYPs in
AAI detoxication in vivo and that of CYP1A1/2 in this reaction in vitro.
Acknowledgements: Supported by GACR (303/09/0472, 305/09/H008) and Ministry of
Education (MSM 0021620808).
XXII. Biochemistry Congress, Martin
233