# Theoretical Study on the Metabolic Mechanism of Heptachlor in Human Cytochrome P450 Enzymes

## TL;DR

This study explores how the insecticide heptachlor is metabolized by human liver enzymes, identifying which enzymes are most likely involved in the process.

## Contribution

The study identifies CYP3A5 as the most likely enzyme for heptachlor metabolism using computational methods.

## Key findings

- HEP binds to CYP enzymes mainly through hydrophobic interactions.
- CYP2A6, CYP3A4, and CYP3A5 are the only enzymes capable of metabolizing HEP.
- CYP3A5 has the lowest energy barrier for HEP metabolism and is likely the primary enzyme involved.

## Abstract

Heptachlor (HEP) is an insecticide metabolized by cytochrome P450 (CYP) enzymes in the human liver, resulting in the formation of heptachlor epoxide (HEPX). HEPX can persist in the human body for a long duration. Therefore, it can be extremely harmful. A comprehensive understanding of HEP’s metabolic fate may provide a theoretical basis for mitigating associated hazards. However, the specific human CYP isoforms that metabolize HEP, and their metabolic mechanisms, remain unclear. In this study, eight human CYP isoforms were used as catalytic enzymes to investigate the metabolic mechanism of HEP using molecular docking, molecular dynamics simulations, and quantum mechanical calculations. These results indicate that HEP primarily binds to CYP enzymes through hydrophobic interactions, and that the binding positions of HEP are determined by the composition and shape of the hydrophobic pockets near the active site. Based on the reaction distance, CYP2A6, CYP3A4, and CYP3A5 were the only three enzymes that could metabolize HEP. The epoxidation of HEP catalyzed by the doublet state of compound I was effectively concerted, and the rate-determining step was the electrophilic attack of the oxygen atom on HEP. The energy barriers of the rate-determining step vary significantly among different enzymes. A comparison of these energy barriers suggested that CYP3A5 is the most likely enzyme for HEP catalysis in humans.