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Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy

Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of... Aristolochic acid (AA), a naturally occurring nephrotoxin and rodent carcinogen, has recently been associated with the development of urothelial cancer in humans. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual susceptibility to this natural carcinogen. We examined the ability of enzymes of rat renal and hepatic cytosolic fractions to activate AA to metabolites forming DNA adducts by the nuclease P1-enhanced version of the 32 P-postlabeling assay. Cytosolic fractions of both these organs generated AA-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin- N 6 -yl)aristolactam I, 7-(deoxyguanosin- N 2 -yl)aristolactam I and 7-(deoxyadenosin- N 6 -yl)aristolactam II were identified as AA-DNA adducts formed from AAI and 7-(deoxyguanosin- N 2 -yl)aristolactam II and 7-(deoxyadenosin- N 6 -yl)aristolactam II were generated from AAII by hepatic cytosol. Qualitatively the same AA-DNA adduct patterns were observed, although at lower levels, upon incubation of AAs with renal cytosol. To define the role of cytosolic reductases in the reductive activation of AA, we investigated the modulation of AA-DNA adduct formation by cofactors, specific inducers or selective inhibitors of the cytosolic reductases, DT-diaphorase, xanthine oxidase (XO) and aldehyde oxidase. The role of the enzymes in AA activation was also investigated by correlating the DT-diaphorase- and XO-dependent catalytic activities in cytosolic sample with the levels of AA-DNA adducts formed by the same cytosolic sample. On the basis of these studies, we attribute most of the cytosolic activation of AA to DT-diaphorase, although a role of cytosolic XO cannot be ruled out. With purified DT-diaphorase, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The binding orientation of AAI in the active site of DT-diaphorase was predicted by computer modeling based on published X-ray structures. The results presented here are the first report demonstrating a reductive activation of carcinogenic AAs by DT-diaphorase. Key words AA, aristolochic acid; AAI, 8-methoxy-6-nitro-phenanthro-(3,4- d )-1,3-dioxolo-5-carboxylic acid; AAII, 6-nitro-phenanthro-(3,4- d )-1,3-dioxolo-5-carboxylic acid; Ah receptor, aryl hydrocarbon receptor; CT-DNA, calf thymus DNA; dAp, deoxyadenosine 3′-monophosphate; dGp, deoxyguanosine 3′-monophosphate; dA-AAI, 7-(deoxyadenosin- N 6 -yl)aristolactam I; dA-AAII, 7-(deoxyadenosin- N 6 -yl)aristolactam II; dG-AAI, 7-(deoxyguanosin- N 2 -yl) aristolactam I; dG-AAII, 7-(deoxyguanosin- N 2 -yl) aristolactam II; K s , apparent dissociation constant; PB, phenobarbital; PEI, polyethylenimine; RAL, relative adduct labeling; XO, xanthine oxidase. © Oxford University Press « Previous | Next Article » Table of Contents This Article Carcinogenesis (2002) 23 (4): 617-625. doi: 10.1093/carcin/23.4.617 » Abstract Free Full Text (HTML) Free Full Text (PDF) Free Classifications Carcinogenesis Services Article metrics Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Stiborová, M. 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Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy

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References (54)

Publisher
Oxford University Press
Copyright
Copyright © 2015 Oxford University Press
ISSN
0143-3334
eISSN
1460-2180
DOI
10.1093/carcin/23.4.617
Publisher site
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Abstract

Aristolochic acid (AA), a naturally occurring nephrotoxin and rodent carcinogen, has recently been associated with the development of urothelial cancer in humans. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual susceptibility to this natural carcinogen. We examined the ability of enzymes of rat renal and hepatic cytosolic fractions to activate AA to metabolites forming DNA adducts by the nuclease P1-enhanced version of the 32 P-postlabeling assay. Cytosolic fractions of both these organs generated AA-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin- N 6 -yl)aristolactam I, 7-(deoxyguanosin- N 2 -yl)aristolactam I and 7-(deoxyadenosin- N 6 -yl)aristolactam II were identified as AA-DNA adducts formed from AAI and 7-(deoxyguanosin- N 2 -yl)aristolactam II and 7-(deoxyadenosin- N 6 -yl)aristolactam II were generated from AAII by hepatic cytosol. Qualitatively the same AA-DNA adduct patterns were observed, although at lower levels, upon incubation of AAs with renal cytosol. To define the role of cytosolic reductases in the reductive activation of AA, we investigated the modulation of AA-DNA adduct formation by cofactors, specific inducers or selective inhibitors of the cytosolic reductases, DT-diaphorase, xanthine oxidase (XO) and aldehyde oxidase. The role of the enzymes in AA activation was also investigated by correlating the DT-diaphorase- and XO-dependent catalytic activities in cytosolic sample with the levels of AA-DNA adducts formed by the same cytosolic sample. On the basis of these studies, we attribute most of the cytosolic activation of AA to DT-diaphorase, although a role of cytosolic XO cannot be ruled out. With purified DT-diaphorase, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The binding orientation of AAI in the active site of DT-diaphorase was predicted by computer modeling based on published X-ray structures. The results presented here are the first report demonstrating a reductive activation of carcinogenic AAs by DT-diaphorase. Key words AA, aristolochic acid; AAI, 8-methoxy-6-nitro-phenanthro-(3,4- d )-1,3-dioxolo-5-carboxylic acid; AAII, 6-nitro-phenanthro-(3,4- d )-1,3-dioxolo-5-carboxylic acid; Ah receptor, aryl hydrocarbon receptor; CT-DNA, calf thymus DNA; dAp, deoxyadenosine 3′-monophosphate; dGp, deoxyguanosine 3′-monophosphate; dA-AAI, 7-(deoxyadenosin- N 6 -yl)aristolactam I; dA-AAII, 7-(deoxyadenosin- N 6 -yl)aristolactam II; dG-AAI, 7-(deoxyguanosin- N 2 -yl) aristolactam I; dG-AAII, 7-(deoxyguanosin- N 2 -yl) aristolactam II; K s , apparent dissociation constant; PB, phenobarbital; PEI, polyethylenimine; RAL, relative adduct labeling; XO, xanthine oxidase. © Oxford University Press « Previous | Next Article » Table of Contents This Article Carcinogenesis (2002) 23 (4): 617-625. doi: 10.1093/carcin/23.4.617 » Abstract Free Full Text (HTML) Free Full Text (PDF) Free Classifications Carcinogenesis Services Article metrics Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Stiborová, M. Articles by Schmeiser, H. H. Search for related content PubMed PubMed citation Articles by Stiborová, M. Articles by Frei, E. Articles by Sopko, B. Articles by Wiessler, M. Articles by Schmeiser, H. H. Related Content Load related web page information Share Email this article CiteULike Delicious Facebook Google+ Mendeley Twitter What's this? Search this journal: Advanced » Current Issue October 2015 36 (10) Alert me to new issues The Journal About this journal Rights & Permissions Dispatch date of the next issue This journal is a member of the Committee on Publication Ethics (COPE) We are mobile – find out more Journals Career Network Impact factor: 5.334 5-Yr impact factor: 5.698 Editor-in-Chief Dr Curtis C Harris, USA View full editorial board For Authors Instructions to authors Online submission Submit Now! Self archiving policy Open access options for authors - visit Oxford Open This journal enables compliance with the NIH Public Access Policy Alerting Services Email table of contents Email Advance Access CiteTrack XML RSS feed Corporate Services Advertising sales Reprints Supplements var taxonomies = ("MED00710"); Most Most Read Apoptosis in cancer Modulation of E-cadherin expression by K-Ras; involvement of DNA methyltransferase-3b Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead Tumor progression and metastasis Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability » View all Most Read articles Most Cited Oxyradicals and DNA damage Sensing and repairing DNA double-strand breaks Functional role of estrogen metabolism in target cells: review and perspectives Apoptosis in cancer Nucleotide excision repair and human syndromes » View all Most Cited articles Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department. Online ISSN 1460-2180 - Print ISSN 0143-3334 Copyright © 2015 Oxford University Press Oxford Journals Oxford University Press Site Map Privacy Policy Cookie Policy Legal Notices Frequently Asked Questions Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan Academic & Professional books Children's & Schools Books Dictionaries & Reference Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks International Education Unit Law Medicine Music Online Products & Publishing Oxford Bibliographies Online Oxford Dictionaries Online Oxford English Dictionary Oxford Language Dictionaries Online Oxford Scholarship Online Reference Rights and Permissions Resources for Retailers & Wholesalers Resources for the Healthcare Industry Very Short Introductions World's Classics function fnc_onDomLoaded() { var query_context = getQueryContext(); PF_initOIUnderbar(query_context,":QS:default","","JRN"); PF_insertOIUnderbar(0); }; if (window.addEventListener) { window.addEventListener('load', fnc_onDomLoaded, false); } else if (window.attachEvent) { window.attachEvent('onload', fnc_onDomLoaded); } var gaJsHost = (("https:" == document.location.protocol) ? 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Journal

CarcinogenesisOxford University Press

Published: Apr 1, 2002

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