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.

• MeSH
• Acetyltransferases metabolism   MeSH
• DNA Adducts chemistry   metabolism   MeSH
• Aryl Hydrocarbon Hydroxylases metabolism   MeSH
• Benz(a)Anthracenes chemistry   metabolism   MeSH
• Biocatalysis MeSH
• Enzymes metabolism   MeSH
• Aristolochic Acids chemistry   metabolism   MeSH
• Humans MeSH
• Models, Molecular * MeSH
• NAD(P)H Dehydrogenase (Quinone) metabolism   MeSH
• Sulfotransferases metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• 3-nitrobenzanthrone MeSH Browser
• Acetyltransferases MeSH
• DNA Adducts MeSH
• aristolochic acid I MeSH Browser
• Aryl Hydrocarbon Hydroxylases MeSH
• Benz(a)Anthracenes MeSH
• Enzymes MeSH
• Aristolochic Acids MeSH
• NAD(P)H Dehydrogenase (Quinone) MeSH
• Sulfotransferases MeSH