TitleExposure to an Environmental Mixture of Polycyclic Aromatic Hydrocarbons Induces Hepatic Cytochrome P450 Enzymes in Mice.
Publication TypeJournal Article
Year of Publication2021
AuthorsStoddard, EG, Nag, S, Martin, J, Tyrrell, KJ, Gibbins, T, Anderson, KA, Shukla, AK, Corley, R, Wright, AT, Smith, JN
JournalChem Res Toxicol
Volume34
Issue9
Pagination2145-2156
Date Published2021 09 20
ISSN1520-5010
KeywordsAnimals, Benzo(a)pyrene, Cytochrome P-450 Enzyme System, Female, Liver, Mice, Microsomes, Liver, Proteome, Proteomics
Abstract

Cytochrome P450 enzymes (CYPs) play an important role in bioactivating or detoxifying polycyclic aromatic hydrocarbons (PAHs), common environmental contaminants. While it is widely accepted that exposure to PAHs induces CYPs, effectively increasing rates of xenobiotic metabolism, dose- and time-response patterns of CYP induction are not well-known. In order to better understand dose- and time-response relationships of individual CYPs following induction, we exposed B6129SF1/J mice to single or repeated doses (2-180 ╬╝mol/kg/d) of benzo[]pyrene (BaP) or Supermix-10, a mixture of the top 10 most abundant PAHs found at the Portland Harbor Superfund Site. In hepatic microsomes from exposed mice, we measured amounts of active CYPs using activity-based protein profiling and total CYP expression using global proteomics. We observed rapid Cyp1a1 induction after 6 h at the lowest PAH exposures and broad induction of many CYPs after 3 daily PAH doses at 72 h following the first dose. Using samples displaying Cyp1a1 induction, we observed significantly higher metabolic affinity for BaP metabolism ( reduced 3-fold), 3-fold higher intrinsic clearance, but no changes to the . Mice dosed with the highest PAH exposures exhibited 1.7-5-fold higher intrinsic clearance rates for BaP compared to controls and higher values indicating greater amounts of enzymes capable of metabolizing BaP. This study demonstrates exposure to PAHs found at superfund sites induces enzymes in dose- and time-dependent patterns in mice. Accounting for specific changes in enzyme profiles, relative rates of PAH bioactivation and detoxification, and resulting risk will help translate internal dosimetry of animal models to humans and improve risk assessments of PAHs at superfund sites.

DOI10.1021/acs.chemrestox.1c00235
Alternate JournalChem Res Toxicol
PubMed ID34472326
PubMed Central IDPMC8820091
Grant ListP41 GM103493 / GM / NIGMS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States