The effect of aristolochic acid I on expression of NAD(P)H:quinone oxidoreductase in mice and rats--a comparative study.
Aristolochic acid is the cause of aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN) and their associated urothelial malignancies. Using Western blotting, we investigated the expression of
quinone oxidoreductase (NQO1), the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI) in mice and rats. In addition, the effect of AAI on the expression of the NQO1 protein and its enzymatic activity in these experimental animal models was examined. We found that NQO1 protein levels in cytosolic fractions isolated from liver, kidney and lung of mice differed from those expressed in these organs of rats. In mice, the highest levels of NQO1 protein and NQO1 activity were found in the kidney, followed by lung and liver. In contrast, the NQO1 protein levels and enzyme activity were lowest in rat-kidney cytosol, whereas the highest amounts of NQO1 protein and activity were found in lung cytosols, followed by those of liver. NQO1 protein and enzyme activity were induced in liver and kidney of AAI-pretreated mice compared with those of untreated mice. NQO1 protein and enzyme activity were also induced in rat kidney by AAI. Furthermore, the increase in hepatic and renal NQO1 enzyme activity was associated with AAI bio-activation and elevated AAI-DNA adduct levels were found in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, our results indicate that AAI can increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential.
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.
František
F
Bárta
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.
Kateřina
K
Levová
Division of Preventive Oncology, National Center for Tumour Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Eva
E
Frei
Research Group Genetic Alteration in Carcinogenesis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Heinz H
HH
Schmeiser
Analytical and Environmental Sciences Division, King's College London, MRC-PHE Centre for Environmental & Health, 150 Stamford Street, London SE1 9NH, United Kingdom.
Volker M
VM
Arlt
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. Electronic address: stiborov@natur.cuni.cz.
Marie
M
Stiborová
D000818:Animals; D034341:Aristolochic Acids / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D034341:Aristolochic Acids; D002273:Carcinogens; C000228:aristolochic acid I; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; C491732:Nqo1 protein, mouse
Aristolochic acid nephropathy; DNA adducts; Metabolic activation; NAD(P):quinone oxidoreductase; Protein expression