Origin of the metabolic site selectivity of 7,12-dimethylbenz[a]anthracene catalysed by the P450 1B1 cytochrome: an in silico protocol

Abstract

7,12-Dimethylbenz[a]anthracene (DMBA) is a significant environmental pollutant belonging to the class of methylated polycyclic aromatic hydrocarbons (MPAHs). It is generated via the incomplete combustion of organic compounds and can induce cancer in a variety of organisms. Therefore, strengthening the study of DMBA metabolism and understanding its potential hazards to human health are of great significance. In this study, human CYP1B1 was employed as the metabolic enzyme to investigate the binding modes, reaction sites and metabolic mechanisms of DMBA by molecular docking, molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. Results indicated that DMBA binds to the active site of CYP1B1 primarily through nonpolar solvation energies (ΔG_nonpolar) in two modes. The π–π interactions formed by Phe231 and Phe268 with DMBA constituted a “sandwich” structure, which acted as a critical stabilizing element in both modes. In both modes, DMBA was metabolized by an electrophilic addition–rearrangement mechanism. Notably, C3 was the electrophilic addition site in mode I, while in mode II, the extra amide–π interaction between Gly329 and DMBA made C4 the preferred metabolic site. Consequently, in path II, the electrophilic addition–rearrangement metabolic process at the C4 site in mode II became the relatively favored metabolic pathway. These results provide theoretical insights into the biological metabolic processes of DMBA and contribute to the comprehension of its toxification potential and cancer risks.