Journal
TOXICOLOGY
Volume 344, Issue -, Pages 7-18Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2016.01.011
Keywords
Aristolochic acid I; Cytochromes P450 1A1 and 1A2; Oxidative detoxification; Reductive activation; DNA adducts
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Funding
- Grant Agency of the Czech Republic [14-18344S]
- Charles University in Prague [UNCE 204025/2012, 570513]
- Cancer Research UK [C313/A14329]
- Cancer Research UK [14329] Funding Source: researchfish
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Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H:quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the P-32-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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