Mechanism of cytochrome P450s mediated interference with glutathione and amino acid metabolisms from halogenated PAHs exposure

Epidemiological evidence indicates that exposure to halogenated polycyclic aromatic hydrocarbons (HPAHs) is associated with many adverse effects. However, the mechanisms of metabolic disorder of HPAHs remains limited. Herein, effects of pyrene (Pyr), and its halogenated derivatives (1-chloropyrene (1-Cl-Pyr), 1-bromopyrene (1-Br-Pyr)) on endogenous metabolic pathways were investigated in human hepatoma (HepG2) and HepG2-derived cell lines expressing various human cytochrome P450s (CYPs). Non-targeted metabolomics results suggested that 1-Br-Pyr and Pyr exposure (625 nM) induced disruption in glutathione and riboflavin metabolism which associated with redox imbalance, through abnormal accumulation of oxidized glutathione, mediated by bioactivation of CYP2E1. Conversely, CYP2C9-mediated 1-Cl-Pyr significantly interfered with glutathione metabolism intermediates, including glycine, L-glutamic acid and pyroglutamic acid. Notably, CYP1A1-mediated Pyr-induced perturbation of amino acid metabolism which associated with nutrition and glycolipid metabolism, resulting in significant upregulation of most amino acids, whereas halogenated derivatives mediated by CYP1A2 substantially downregulated amino acids. In conclusion, this study suggested that Pyr and its halogenated derivatives exert potent effects on endogenous metabolism disruption under the action of various exogenous metabolic enzymes (CYPs). Thus, new evidence was provided to toxicological mechanisms of HPAHs, and reveals potential health risks of HPAHs in inducing diseases caused by redox and amino acid imbalances. Environmental Implication This study provides novel evidence that upon metabolic activation by CYPs, HPAH exhibited higher cytotoxicity and caused severe endogenous metabolic disturbances. Our findings revealed potential health risks of HPAHs in inducing diseases caused by redox and amino acid imbalances and alert us to pay more attention to exposure of HPAHs, meanwhile provide a new theoretical basis for assessing the health risks of HPAH exposure in different populations with differential CYPs expression. Environmental implication Halogenated polycyclic aromatic hydrocarbons (HPAHs) are widely distributed in various environmental media and biological matrices, and tends to cause strong adverse health effects in humans, such as tumorigenic, carcinogenic, and mutagenic. Herein, we found that upon metabolic activation by specific cytochrome P450s (CYPs), HPAH exhibited higher cytotoxicity and caused severe endogenous metabolic disturbances. Our findings alert us to pay more attention to exposure of HPAHs and provide a new theoretical basis for assessing the health risks of HPAH exposure in different populations with differential CYPs expression.