Mechanism of 7H-Dibenzo[c,g]carbazole Metabolism in Cytochrome P450 1A1: Insights from Computational Studies

7H-Dibenzo[c,g]carbazole (DBC) is a prevalent environmental contaminant that induces tumorigenesis in several experimental animals. Recently, it has been utilized to develop high-performance solar cells and organic phosphorescent materials.  It is imperative to strengthen investigations of DBC metabolism to understand its potential risks to human health. In this study, human CYP1A1 was employed as the metabolic enzyme to investigate the metabolic mechanism of DBC by molecular docking, molecular dynamics (MD) simulation, and quantum mechanical (QM) calculation. The results indicate that DBC binds to CYP1A1 in two modes (mode 1 and mode 2) mainly through nonpolar solvation energies (ΔGnonpolar). The formation of the two binding modes is attributed to the anchoring effect of the hydrogen bond formed by DBC with Asp320 (mode 1) or Ser116 (mode 2). Mode 1 is a "reactive" conformation, while mode 2 is not considered a "reactive" conformation. C5 is identified as the dominant site, and the pyrrole nitrogen cannot participate in the metabolism. DBC is metabolized mainly by a distinct electrophilic addition-rearrangement mechanism, with an energy barrier of 21.74kcal/mol. The results provide meaningful insights into the biometabolic process of DBC and contribute to understanding its environmental effects and health risks.Environmental Implications7H-Dibenzo[c,g]carbazole (DBC) is a prevalent environmental pollutant, which has been classified as a Group 2B carcinogen by the International Agency for Research on Cancer (IARC). In recent years, it is used to develop high-performance solar cells and organic phosphorescent materials. However, the biometabolic process of DBC remains unclear. Our research reveals the binding mode, regioselectivity and mechanism of metabolism of DBC in human CYP1A1 at the microscopic level. These findings contribute to the understanding of the biometabolic process of DBC and provide a theoretical basis for the hazard assessment of such substances.