1-Nitropyrene Metabolism and Health Risk: Identification of Key Enzymes, Pathways, and Metabolites Using a Multimethod Approach.

Polycyclic aromatic hydrocarbon (PAH) derivatives have a widespread presence in the environment and even the human body, but their metabolism and potential risk remain unclear. In this study, we used molecular dynamics simulations and density functional theory to calculate the metabolic mechanism of 1-nitropyrene (1-NP), an important PAH derivative. The results showed that cytochrome P450 enzymes (CYPs) can metabolize 1-NP, with CYP 2A13 and CYP 2E1 being important enzyme isoforms, because they had lower binding affinities (-16.48 and -13.90 kcal/mol) to 1-NP than other CYPs (-2.38 to -7.89 kcal/mol). Additionally, these CYPs can metabolize 1-NP through epoxidation and hydroxylation pathways. Compared to hydroxylation, epoxidation had a lower energy barrier of 9.42 kcal/mol, and 4,5-epoxide-1-nitropyrene and 9,10-epoxide-1-nitropyrene were identified as the major epoxidation products through electrophilic addition. In addition, 6-hydroxy-1-nitropyrene and 8-hydroxy-1-nitropyrene were the major hydroxylated metabolites. Health risks revealed that electrophilicity of epoxides increased the risk of binding to DNA, and both 1-NP and its four important metabolites cause adverse effects on the gastrointestinal system and lung. In summary, this study revealed the metabolic mechanism of 1-NP by human CYPs and formation of toxic metabolites, and more attention should be paid to the nitro-derivatives of PAHs in the future.