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

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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 D O–C, D O–H, and angle A C–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.

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