Cytochrome P4501A1-Catalyzed Regioselective Activation Mechanism of PAHs and Their Nitrogen-Containing Derivatives

Polycyclic aromatic hydrocarbons (PAHs) and their nitrogen-containing derivatives are persistent environmental pollutants prevalent in combustion byproducts and industrial waste. Human cytochrome P4501A1 (CYP1A1), a key isoform within the cytochrome P450 enzyme family, plays a pivotal role in its oxidative metabolism. Here, a high-level quantum mechanics/molecular mechanics (QM/MM) computational approach was employed to elucidate the regioselective activation mechanisms of three representative compounds: carbazole, fluorene, and 2-aminofluorene. We show that CYP1A1 preferentially activates these compounds through competitive electrophilic addition and hydrogen abstraction pathways. We identify different regioselectivities among the three model compounds. Correlation analyses reveal that distance DO–C, DO–H, and angle AC–O–Fe are the principal determinants of regioselectivity. The calculated reactivity order is 2-aminofluorene > carbazole > fluorene. These findings provide mechanistic insight into the enzymatic transformation of PAHs and their nitrogen-containing derivatives in human cells, contributing to a more accurate assessment of their potential health risks.