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.