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Int. J. Mol. Sci. 2014, 15(6), 10271-10295; doi:10.3390/ijms150610271
Review

Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

1,* , 2
,
3
,
4
 and
1
1 Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, CZ-12843, Prague 2, Czech Republic 2 Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 3 Radiopharmaceutical Chemistry E030, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 4 Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental & Health, King's College London, 150 Stamford Street, London SE1 9NH, UK
* Author to whom correspondence should be addressed.
Received: 24 March 2014 / Revised: 30 May 2014 / Accepted: 30 May 2014 / Published: 10 June 2014
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Abstract

This review summarizes the results found in studies investigating the enzymatic activation of two genotoxic nitro-aromatics, an environmental pollutant and carcinogen 3-nitrobenzanthrone (3-NBA) and a natural plant nephrotoxin and carcinogen aristolochic acid I (AAI), to reactive species forming covalent DNA adducts. Experimental and theoretical approaches determined the reasons why human NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P450 (CYP) 1A1 and 1A2 have the potential to reductively activate both nitro-aromatics. The results also contributed to the elucidation of the molecular mechanisms of these reactions. The contribution of conjugation enzymes such as N,O-acetyltransferases (NATs) and sulfotransferases (SULTs) to the activation of 3-NBA and AAI was also examined. The results indicated differences in the abilities of 3-NBA and AAI metabolites to be further activated by these conjugation enzymes. The formation of DNA adducts generated by both carcinogens during their reductive activation by the NOQ1 and CYP1A1/2 enzymes was investigated with pure enzymes, enzymes present in subcellular cytosolic and microsomal fractions, selective inhibitors, and animal models (including knock-out and humanized animals). For the theoretical approaches, flexible in silico docking methods as well as ab initio calculations were employed. The results summarized in this review demonstrate that a combination of experimental and theoretical approaches is a useful tool to study the enzyme-mediated reaction mechanisms of 3-NBA and AAI reduction.
Keywords: nitro-aromatics; 3-nitrobenzanthrone; aristolochic acid I; DNA adducts; molecular modeling; NAD(P)H:quinone oxidoreductase; cytochrome P450 nitro-aromatics; 3-nitrobenzanthrone; aristolochic acid I; DNA adducts; molecular modeling; NAD(P)H:quinone oxidoreductase; cytochrome P450
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Stiborová, M.; Frei, E.; Schmeiser, H.H.; Arlt, V.M.; Martínek, V. Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches. Int. J. Mol. Sci. 2014, 15, 10271-10295.

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Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert