In vitro evaluation of the effects of emerging contaminants on human cytochrome P450: prediction of toxicokinetic parameters and xenobiotic-drug interactions

• Grant number: 24/20783-4
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Analytical Chemistry
• Principal Investigator: Anderson Rodrigo Moraes de Oliveira
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Natália Valadares de Moraes

Abstract

In this new proposal, we aim to continue the project initiated previously (FAPESP 2021/10098-4), whose term ended on July 31, 2024. The main objective of this new proposal is to perform, in vitro, the metabolism of emerging contaminants, by the main cytochrome P450 (CYP450) enzymes involved in drug metabolism. In addition, the ability of these molecules to decrease the activity of these enzymes will be evaluated. In order to improve the prediction of inhibition and interaction in vivo, we will use PBTK (physiologically-based toxicokinetics) modeling in this work. This part of the study will be conducted in collaboration with Prof. Natália V. de Moraes, from the University of Florida (USA). The in vitro kinetic data generated will allow the subsequent in vivo extrapolation and the prediction of interactions, thus contributing to a better understanding of the risks associated with these compounds. Our motivation for continuing this project is based on the results of previous studies, which indicated an important participation of CYP450 enzymes in the metabolism of the substrates evaluated and great potential for inhibition of these enzymes. Although there are studies evaluating the toxicity, ecotoxicity and environmental impact of emerging contaminants, and despite human contact with these molecules, whether in the workplace or through the ingestion of contaminated food or water, there are still few studies evaluating the interaction of these compounds with CYP450 enzymes using human models. In this context, our research group has stood out as a pioneer. In this new proposal, which will be detailed in the following paragraphs, our studies will focus on the analysis of three classes of emerging contaminants: (i) pesticides, including glyphosate, malathion, cyflumetofen and clethodim; (ii) perfluoroalkyl and polyfluoroalkyl compounds (PFAS), such as PFOA, PFOS, HFPO-DA, DONA and F-53B; and (iii) the main active ingredients used in photoprotection formulations, which include octinoxate, octocrylene, avobenzone, benzophenone-3, homosalate and octysalate. (AU)