Mechanisms of enzyme-catalyzed reduction of two carcinogenic nitro-aromatics, 3-nitrobenzanthrone and aristolochic acid I: Experimental and theoretical approaches.

TitleMechanisms of enzyme-catalyzed reduction of two carcinogenic nitro-aromatics, 3-nitrobenzanthrone and aristolochic acid I: Experimental and theoretical approaches.
Publication TypeJournal Article
Year of Publication2014
AuthorsStiborova M, Frei E, Schmeiser HH, Arlt VM, Martínek V
JournalInt J Mol Sci
Volume15
Issue6
Pagination10271-95
Date Published06/2014
ISSN1422-0067
KeywordsAcetyltransferases, Animals, Aristolochic Acids, Aryl Hydrocarbon Hydroxylases, Benz(a)Anthracenes, Biocatalysis, DNA Adducts, Enzymes, Humans, Models, Molecular, NAD(P)H Dehydrogenase (Quinone), Sulfotransferases
Abstract

UNLABELLED: 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.

DOI10.3390/ijms150610271
Alternate JournalInt J Mol Sci
PubMed ID24918288
PubMed Central IDPMC4100152
Grant List / / Wellcome Trust / United Kingdom
/ / Cancer Research UK / United Kingdom