DMD Noab BioDiscoveries - Shaping Drug Discovery

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on May 19, 2006; DOI: 10.1124/dmd.106.009373

This Article
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
dmd.106.009373v1
34/8/1398    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stiborova, M.
Right arrow Articles by Arlt, V. M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stiborova, M.
Right arrow Articles by Arlt, V. M


Received for publication January 19, 2006.
Revised May 15, 2006.
Accepted for publication May 15, 2006.

THE ENVIRONMENTAL POLLUTANT AND CARCINOGEN 3-NITROBENZANTHRONE AND ITS HUMAN METABOLITE 3-AMINOBENZANTHRONE ARE POTENT INDUCERS OF RAT HEPATIC CYTOCHROMES P450 1A1 AND -1A2 AND NAD(P)H:QUINONE OXIDOREDUCTASE

Marie Stiborova 1*, Helena Dracinska 1, Jana Hajkova 1, Pavla Kaderabkova 1, Eva Frei 2, Heinz H Schmeiser 2, Pavel Soucek 3, David H Phillips 4, Volker M Arlt 5

1 Charles University, Faculty of Science 2 German Cancer Research Center 3 National Institute of Public Health 4 nstitute of Cancer Research 5 Institute of Cancer Research

* Address correspondence to: E-mail: stiborov{at}natur.cuni.cz

Abstract

3-Nitrobenzanthrone (3-NBA), a suspected human carcinogen occurring in diesel exhaust and air pollution and its human metabolite 3-aminobenzanthrone (3-ABA) were investigated for their ability to induce biotransformation enzymes in rat liver and the influence of such induction on DNA adduct formation by the compounds. Rats were treated (i.p.) with 0.4, 4 or 40 mg/kg body weight of 3-NBA or 3-ABA. When hepatic cytosolic fractions from rats treated with 40 mg/kg body weight of 3-NBA or 3-ABA were incubated with 3-NBA, DNA adduct formation, measured by 32P-postlabelling analysis, was 10-fold higher in incubations with cytosols from pretreated rats than with controls. The increase in 3-NBA-derived DNA adduct formation corresponded to a dose-dependent increase in protein levels and enzymatic activity of NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is the major enzyme reducing 3-NBA in human and rat livers. Incubations of 3-ABA with hepatic microsomes of rats treated with 3-NBA or 3-ABA (40 mg/kg body weight) led to an up to 12-fold increase in 3-ABA-derived DNA adduct formation compared to controls. The observed stimulation of DNA adduct formation by both compounds was attributed to their potential to induce protein expression and enzymatic activity of cytochromes P450 1A1 and/or -1A2 (CYP1A1/2), the major enzymes responsible for 3-ABA activation in human and rat livers. Collectively, these results demonstrate for the first time that by inducing hepatic NQO1 and CYP1A1/2, both 3-NBA and 3-ABA increase the enzymatic activation of these two compounds to reactive DNA adduct forming species, thereby enhancing their own genotoxic potential.


Key words: bioactivation, CYP1A, DNA adducts, enzyme induction, induction, NAD(P)H-quinone oxidoreductase


This article has been cited by other articles:


Home page
 MutagenesisHome page
V. M. Arlt, J. Gingerich, H. H. Schmeiser, D. H. Phillips, G. R. Douglas, and P. A. White
Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaTMMouse and lung epithelial cells derived from MutaTMMouse
Mutagenesis, November 1, 2008; 23(6): 483 - 490.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
V. M. Arlt, M. Stiborova, C. J. Henderson, M. Thiemann, E. Frei, D. Aimova, R. Singh, G. Gamboa da Costa, O. J. Schmitz, P. B. Farmer, et al.
Metabolic activation of benzo[a]pyrene in vitro by hepatic cytochrome P450 contrasts with detoxification in vivo: experiments with hepatic cytochrome P450 reductase null mice
Carcinogenesis, March 1, 2008; 29(3): 656 - 665.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Aimova, L. Svobodova, V. Kotrbova, B. Mrazova, P. Hodek, J. Hudecek, R. Vaclavikova, E. Frei, and M. Stiborova
The Anticancer Drug Ellipticine Is a Potent Inducer of Rat Cytochromes P450 1A1 and 1A2, Thereby Modulating Its Own Metabolism
Drug Metab. Dispos., October 1, 2007; 35(10): 1926 - 1934.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
V. M. Arlt, H. Glatt, G. Gamboa da Costa, J. Reynisson, T. Takamura-Enya, and D. H. Phillips
Mutagenicity and DNA Adduct Formation by the Urban Air Pollutant 2-Nitrobenzanthrone
Toxicol. Sci., August 1, 2007; 98(2): 445 - 457.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.