title: Mechanisms of enzyme-catalyzed reduction of two carcinogenic nitro-aromatics, 3-nitrobenzanthrone and aristolochic acid I: Experimental and theoretical approaches.
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
  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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, CZ-12843, Prague 2, Czech Republic. stiborov@natur.cuni.cz.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. eva.frei@nct-heidelberg.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.affiliation: Radiopharmaceutical Chemistry E030, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. h.schmeiser@dkfz-heidelberg.de.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental & Health, King's College London, 150 Stamford Street, London SE1 9NH, UK. volker.arlt@kcl.ac.uk.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, CZ-12843, Prague 2, Czech Republic. vacmar@natur.cuni.cz.
authors.forename: Václav
authors.initials: V
authors.lastname: Martínek
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D034341:Aristolochic Acids / Q000737:chemistry / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001551:Benz(a)Anthracenes / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D001551:Benz(a)Anthracenes; D018736:DNA Adducts; D004798:Enzymes; C000228:aristolochic acid I; D001189:Aryl Hydrocarbon Hydroxylases; D016660:NAD(P)H Dehydrogenase (Quinone); D000123:Acetyltransferases; D015238:Sulfotransferases; C117220:3-nitrobenzanthrone