Next Article in Journal
Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism
Next Article in Special Issue
Prediction of Protein S-Nitrosylation Sites Based on Adapted Normal Distribution Bi-Profile Bayes and Chou’s Pseudo Amino Acid Composition
Previous Article in Journal
The Calcium Phosphate Matrix of FGF-2-Apatite Composite Layers Contributes to Their Biological Effects
Previous Article in Special Issue
The Application of an Emerging Technique for Protein–Protein Interaction Interface Mapping: The Combination of Photo-Initiated Cross-Linking Protein Nanoprobes with Mass Spectrometry
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
View Full-Text   |   Download PDF [2569 KB, uploaded 19 June 2014]   |   Browse Figures

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 (CC BY 3.0).
SciFeed

Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
EndNote |
RIS
MDPI and ACS Style

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.

View more citation formats

Related Articles

Article Metrics

For more information on the journal, click here

Comments

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