Pharmacogenomics of Drug Metabolism in Mice: The Impact of Environmental Pollutants

Abstract

Interindividual variability in drug response arises from the complex interplay between inherited pharmacogenomic traits and environmental exposures. While genetic polymorphisms in cytochrome P450 (CYP450) enzymes are well-established determinants of metabolic capacity, the modulatory effects of environmental pollutants on these pharmacogenomic profiles remain insufficiently quantified in murine models. This systematic review and quantitative synthesis examined the impact of heavy metals, polycyclic aromatic hydrocarbons (PAHs), dioxins, pesticides, and airborne particulate matter on CYP450-mediated drug metabolism in mice, with emphasis on exposure-specific mechanisms and pharmacogenomic interactions. A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar (2000–2024) identified 85 relevant studies, of which 42 met inclusion criteria and provided quantitative data. Dioxins produced the most potent CYP1A1 induction (mean fold change: 5.8 ± 2.3; n = 8 studies), followed by PAHs (4.2 ± 1.8; n = 12), airborne PM2.5 (3.5 ± 1.2; n = 4), and heavy metals (2.1 ± 0.9; n = 6), whereas heavy metals also induced CYP2E1 (2.9 ± 1.1; n = 7) and pesticides induced CYP3A11 (2.0 ± 0.7; n = 6). Three primary mechanistic pathways were identified: nuclear receptor-mediated transcriptional induction (AhR, CAR, PXR), epigenetic modification (DNA methylation, histone alteration), and oxidative stress with direct protein damage. Genetic background significantly modified pollutant responses, with Cyp1a1-null and humanized CYP transgenic mice demonstrating strain-specific metabolic outcomes. These findings demonstrate that environmental pollutants profoundly reshape pharmacogenomic landscapes of drug metabolism in mice through compound-specific, dose-dependent, and genetically modified pathways, supporting the integration of exposomic data into pharmacogenomic frameworks to predict drug response variability in contaminated environments. Keywords: pharmacogenomics; drug metabolism; environmental pollutants; cytochrome P450; mice; xenobiotics; heavy metals; polycyclic aromatic hydrocarbons; exposome.