Origin of metabolites diversity and selectivity of P450 catalyzed benzo[a]pyrene metabolic activation

Polycyclic Aromatic Hydrocarbon (PAHs) presents one of the most abundant class of environmental pollutants. Recent study shows a lab-synthesized PAHs derivative, helicenium, can selectively kill cancer cells rather than normal cells, calling for the in-depth understanding of the metabolic process. However, the origin of metabolites diversity and selectivity of P450 catalyzed PAHs metabolic activation is still unclear to a great extent. Here we systematically investigated P450 enzymes catalyzed activation mechanism of a representative PAHs, benzo[a]pyrene (BaP), and found the corresponding activation process mainly involves two elementary steps: electrophilic addition and epoxidation. Electrophilic addition step is evidenced to be rate determining step. Two representative binding modes of BaP with P450 were found, which enables the electrophilic addition of Heme (FeO) to almost all the carbons of BaP. This electrophilic addition was proposed to be accelerated by the P450 enzyme environment when compared with the gas phase and water solvent. To dig deeper on the origin of metabolites diversity, we built several linear regression models to explore the structural-energy relationships. The selectivity was eventually attributed to the integrated effects of structural (e.g. O-C distance and O-C-Fe angle) and electrostatic parameters (e.g. charge of C and O) from both BaP and P450.