Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo.

Abstract

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 (32)P-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.

• Authors: Helena Dračínská, František Bárta, Kateřina Levová, Alena Hudecová, Michaela Moserová, Heinz H Schmeiser, Klaus Kopka, Eva Frei, Volker M Arlt, Marie Stiborová
• Journal: Toxicology (Toxicology) Vol. 344-346 Pg. 7-18 (Feb 17 2016) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 26845733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Aristolochic Acids
• Carcinogens
• DNA Adducts
• aristolochic acid I
• CYP1A1 protein, human
• CYP1A2 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2

Topics

• Animals
• Aristolochic Acids (toxicity)
• Carcinogens (toxicity)
• Cytochrome P-450 CYP1A1 (biosynthesis)
• Cytochrome P-450 CYP1A2 (biosynthesis)
• DNA Adducts (antagonists & inhibitors, biosynthesis)
• Enzyme Induction (drug effects, physiology)
• Male
• Rats
• Rats, Wistar