Human CYP1A2 metabolism of organophosphorus pesticides and nerve agent surrogates

Abstract

CYP1A2 contributes 13-15% of hepatic CYP450 content and plays a critical role in the metabolism of approximately 10% of pharmaceutical drugs in the human body. CYP1A2 has been previously reported to bioactivate and detoxify both the thion (P=S) and oxon (P=O) forms of organophosphorus (OP) compounds. In this study, we determined the capacity of CYP1A2 to degrade OP compounds using LC-MS/MS, as well as the inhibition of its activity by OP compounds using the previously developed pFluor50 assay. CYP1A2 was selective in metabolizing thions over oxons, and several OP compounds inhibited its activity in a time- and dose-dependent manner. To further investigate the mechanism of CYP1A2-OP interactions, molecular docking studies were performed using a crystal structure of CYP1A2 (PDB ID: 2HI4). Linear correlation analysis between CYP1A2 inhibition at 10 M with 30 minute preincubation and the % OP compound remaining at 2 hours (R = -0.71, P<0.001) showed a moderate but significant correlation. Based on these findings, CYP1A2 was identified as a potential bioscavenger for OP compound metabolism, supporting the future integration of experimental and in silico data for developing artificial intelligence (AI) / machine learning (ML) models for prediction of CYP1A2-mediated metabolism of existing and emerging OP compounds, including those of toxicological and chemical warfare relevance.