Nitro-polycyclic aromatic hydrocarbons (NO2PAHs) generated and released in combustion systems are environmental pollutants with strong mutagenic and carcinogenic properties. The mutagenic nitro derivative of benzo(a)pyrene (BaP) includes 1- and 3-nitroform, 1,6- and 3,6-dinitroisomers. Compared to the mononitro form, the dinitro form is a more potent mutagen. The mutagenicity of mono- and dinitro-BaP with a nitro group at position 3 is much more potent than that with the nitro group at position 1. The nitro group of NO2PAHs is reductively metabolized to hydroxylamine (HONPAHs) and then acetylated by acetyltransferase (AcONPAHs) to form nitronium ions (+NPAHs), which bind mainly to the guanine 8 positions of DNA. Since the nitro group is reductively activated, the nitro group's reductive property is useful in evaluating mutagenicity. However, the difference in mutagenicity between the 1-nitro and 3-nitro compounds cannot be explained by the reducing property. We hypothesized that the difference in the position of the nitro group would significantly affect the DNA-binding mode of the reductively activated product. Therefore, we explored the stable conformation of AcONPAHs for each nitro compound by docking calculations targeting the DNA base-pair layers. We optimized the docking pose structure in which the distance (dis) between the nitrogen of AcONPAHs and the 8-position of guanine is 5 Å and obtained the distance of the structure with the minimum binding free energy. As a result, mono- and dinitro-BaPs with a nitro group at the 3-position rather than the 1-position are more likely to form an adduct with DNA due to the closer distance between the reductively activated form and the guanine 8-position. For both 1- and 3-nitro-BaP with a cyano group at 6-position, the reductively activated form of the 3-nitro compound, which has strong mutagenic activity, was closer to the guanine 8 positions. These results indicate that the strength of mutagenicity of NO2PAH is greatly influenced not only by the reduction properties of the nitro group but also by the distance between the metabolic activator and DNA.

Docking study on the position of nitro groups affecting the mutagenicity of nitroarenes

ACS Fall 2021

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