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

被引：22

作者：

Dracinska, Helena ^{[1
]}

Barta, Frantisek ^{[1
]}

Levova, Katerina ^{[1
]}

Hudecova, Alena ^{[1
]}

Moserova, Michaela ^{[1
]}

Schmeiser, Heinz H. ^{[2
]}

Kopka, Klaus ^{[2
,3
]}

Frei, Eva ^{[1
]}

Arlt, Volker M. ^{[4
]}

Stiborova, Marie ^{[1
]}

机构：

[1] Charles Univ Prague, Fac Sci, Dept Biochem, Albertov 2030, CZ-12840 Prague, Czech Republic

[2] German Canc Res Ctr, Div Radiophannaceut Chem, Heidelberg, Germany

[3] German Canc Consortium DKTK, Heidelberg, Germany

[4] Kings Coll London, MRC PHE Ctr Environm & Hlth, Analyt & Environm Sci Div, London WC2R 2LS, England

来源：

TOXICOLOGY | 2016年 / 344卷

关键词：

Aristolochic acid I; Cytochromes P450 1A1 and 1A2; Oxidative detoxification; Reductive activation; DNA adducts; P-32 POSTLABELING ANALYSIS; METABOLIC-ACTIVATION; REDUCTIVE ACTIVATION; NAD(P)H/QUINONE OXIDOREDUCTASE; UROTHELIAL CANCER; O-DEMETHYLATION; RISK-FACTOR; SUDAN-I; NEPHROPATHY; DETOXICATION;

D O I：

10.1016/j.tox.2016.01.011

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：7 / 18

页数：12

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