Why do the different positions of nitro groups in nitro-polycyclic aromatic hydrocarbons significantly affect their mutagenicity?


Increasing urbanization has led to several human activities that pollute the environment with various contaminants, including polycyclic aromatic hydrocarbons (PAHs). PAHs are persistent pollutants with a wide spectrum of biological toxicity due to their intrinsic features; removing PAHs from the environment has been a global problem. PAH contaminants are present in both aquatic and terrestrial environments, as well as in the atmosphere. Polycyclic aromatic hydrocarbons (PAHs) are organic pollutants made up of two or more fused aromatic rings of carbon and hydrogen atoms that are generally colorless, white, or light yellow solid substances. Many PAHs are mutagenic, carcinogenic, teratogenic, and immunotoxic to living species, including bacteria, animals, and people. PAHs have been classified into four groups by the International Agency for Research on Cancer (IARC), with group 1 being carcinogenic to humans, group 2A being probably carcinogenic to humans, group 2B being possibly carcinogenic to humans, and group 3 being not classifiable as carcinogenic to humans.

Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) are polycyclic aromatic hydrocarbons (PAHs) with at least one nitro-functional group on the aromatic benzene ring. Nitro-PAHs are mostly produced due to incomplete combustion and pyrolysis of fossil fuels and biomass. As a result, they, along with PAHs, are discharged into the environment by automobiles, factories, domestic stoves/heaters, waste incinerators, and natural fires. Benzo[a]pyrene is a polycyclic aromatic hydrocarbon produced when organic matter is incompletely burned. The metabolites of BaP are mutagenic and extremely carcinogenic, and the IARC classifies it as a Group 1 carcinogen.

A series of 1- and 3-nitroBaPs with a substituent at the C6 position that affects the reducing properties of the nitro groups were synthesized and evaluated for their mutagenicity in a new study published in the journal Toxicology and Applied Pharmacology by Professor Kiyoshi Fukuhara from Showa University School of Pharmacy and co-authors Akiko Ohno, Yoshio Okiyama, and Dr. Akihiko Hirose from National Institute of Health Sciences. The authors conducted an in silico analysis to determine if the location of the nitro group affects nitro-reduction and DNA adduct formation, which is known to be a predictor of the mutagenic effects of nitroBaPs.

Because NO2PAHs express mutagenicity via reductive metabolic activation of the nitro group, the ease of the first and second one-electron reduction of NO2PAH is the rate-limiting component in the reductive metabolism of the nitro group, is critical in evaluating mutagenicity. The intensity of mutagenicity, which changes depending on the added nitro group’s location, cannot be determined just by the nitro group’s reducibility to a metabolically active state. The researchers discovered that the distance between a NO2BaP’s reductively active metabolite and guanine C8 when it introduces into DNA significantly impacts its mutagenicity. The optimized structures of the reductive active metabolites of 1-NO2 and 3-NO2BaP intercalated into DNA base pairs indicated that guanine C8, the DNA alkylation target, was closer to the nitrogen in the active metabolite of 3-NO2BaP than to the nitrogen in the active metabolite of 1-NO2BaP. According to the findings, the higher mutagenicity of 3,6-diNO2BaP compared to 1,6-diNO2BaP in the TA98 and TA98NR strains of S. Typhimurium is due not only to the relative ease of reductive activation of the nitro group at the C3 position due to the electron-withdrawing effect of the nitro group at the C6 position but also to structural characteristics of the reductive metabolite The fact that 3,6- diNO2BaP promotes lung cancer and is highly mutagenic is probably likely related to the reductive active metabolite’s proclivity to form adducts with DNA.

The study by Professor Kiyoshi Fukuhara and colleagues gives new knowledge on predicting the mutagenicity of a NO2PAH based on its chemical structure. Future studies will focus on investigating the processes of metabolic activation and testing the interactions between the metabolite and DNA to anticipate and assess the mutagenicity and carcinogenicity of PAHs and NO2PAHs.

Why do the different positions of nitro groups in nitro-polycyclic aromatic hydrocarbons significantly affect their mutagenicity? - Medicine Innovates

About the author

Kiyoshi Fukuhara has been a Professor in the Division of Organic and Medicinal Chemistry at the Showa University School of Pharmacy, Japan, since 2013. He started his career as a researcher at the National Institute of Health Sciences in 1986. He received his Ph.D. degree in 1995 in pharmaceutical sciences from Tokyo University. His work has contributed to developing a new type of preventive and therapeutic agent based on natural polyphenol. His strategy is to change natural polyphenol’s stereochemistry and physical property to enhance the biological activities essential for regulating disease progression. He also focuses on chemical research in the toxicology of environmental carcinogens and the adverse effects of nanomaterials and dietary supplements.


Ohno A, Okiyama Y, Hirose A, Fukuhara K. The position of the nitro group affects the mutagenicity of nitroarenes. Toxicology and Applied Pharmacology. 2022 Apr 15;441:115974.

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