title: 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
  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: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors: Helena
authors: H
authors: Dračínská
authors: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors: František
authors: F
authors: Bárta
authors: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors: Kateřina
authors: K
authors: Levová
authors: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors: Alena
authors: A
authors: Hudecová
authors: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors: Michaela
authors: M
authors: Moserová
authors: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Heinz H
authors: HH
authors: Schmeiser
authors: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Klaus
authors: K
authors: Kopka
authors: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors: Eva
authors: E
authors: Frei
authors: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, London, United Kingdom.
authors: Volker M
authors: VM
authors: Arlt
authors: Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic. Electronic address: stiborov@natur.cuni.cz.
authors: Marie
authors: M
authors: Stiborová
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D018736:DNA Adducts / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; C000228:aristolochic acid I; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2
keywords: Aristolochic acid I; Cytochromes P450 1A1 and 1A2; DNA adducts; Oxidative detoxification; Reductive activation