ABSTRACT: In recent years, plastic and especially microplastic in the oceans have caused huge problems to marine flora and fauna. Recently, such particles have also been detected in blood, breast milk, and placenta, underlining their ability to enter the human body presumably by the food chain and other yet unknown mechanisms. In addition, plastic contains plasticizers, antioxidants or lubricants, whose impact on human health is also under investigation. At the cellular level, the most important enzymes involved in the metabolism of xenobiotic compounds are the cytochrome P450 monooxygenases (CYPs). Despite their extensive characterization in the maintenance of cellular balance, their interaction with plastic and related products is elusive. In this study, the possible interactions between several plastic-related compounds and one of the most important cytochromes, CYP2C19, were analyzed. By applying virtual compound screening and molecular docking to more than 1000 commercially available plastic-related compounds, we identified candidates which are likely to interact with this protein. A growth inhibition assay confirmed their cytotoxic activity on a CYP2C19-transfected hepatic cell line. Subsequently, we studied the effect of selected compounds on the transcriptome-wide gene expression level by RNA-sequencing. Three candidate molecules, (i.e., 2,2'-methylene bis(6-tert-butyl-4-methylphenol; 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl) ethane; 2,2'-methylene bis(6-cyclohexyl-4-methylphenol), which bound with high affinity to CYP2C19 in silico, exerted profound cytotoxicity in vitro, and interacted with several metabolic pathways of which the ‘cholesterol biosynthesis process’ was most affected. In addition, other affected pathways involving mitosis, DNA replication and inflammation have been identified, suggesting an increase of hepatotoxicity. These discoveries suggest that plastic-related compounds can damage the liver through their influence on several pathways.
