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

Helena Dračínská,František Bárta,Heinz H Schmeiser,Michaela Moserová,Volker M Arlt,Marie Stiborová,Eva Frei,Kateřina Levová,Alena Hudecová,Klaus Kopka

doi:10.1016/j.tox.2016.01.011

Helena Dračínská, František Bárta + Show 8 more

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https://doi.org/10.1016/j.tox.2016.01.011

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Abstract

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.

Highlights

Aristolochic acid (AA) is a herbal drug prepared from plants of the Aristolochia genus containing nitrophenanthrene carboxylic acids, of which 8-methoxy-6-nitro-phenanthro-(3,4d)-1,3-dioxolo-5-carboxylic acid (Fig. 1) and 6-nitro-phenanthro(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAII) are the predominant components (Arlt et al, 2002b)
Using the nuclease P1 version of 32P-postlabeling assay, all liver, kidney and lung samples from rats treated with Aristolochic acid I (AAI) showed an adduct pattern similar to that found in kidney tissue from aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN) patients (Arlt et al, 2002b; Nortier et al, 2000; Schmeiser et al, 1996, 1997, 2012)
The results of this study demonstrate that AAI-DNA adducts are formed in vivo in all organs tested, both in rats treated with AAI alone or in combination with the inducer Sudan I

Summary

Introduction

Aristolochic acid (AA) is a herbal drug prepared from plants of the Aristolochia genus containing nitrophenanthrene carboxylic acids, of which 8-methoxy-6-nitro-phenanthro-(3,4d)-1,3-dioxolo-5-carboxylic acid (aristolochic acid I, AAI) (Fig. 1) and 6-nitro-phenanthro(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAII) are the predominant components (Arlt et al, 2002b). Exposure to AA has been found to be the cause of a similar type of renal disease, Balkan endemic nephropathy (BEN) and its associated occurrence of urothelial malignancy (Arlt et al, 2007; Grollman et al, 2007). This disease is endemic in certain rural areas of Balkan countries near the tributaries of the Danube river (Schmeiser et al, 2012)

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