Exposure to an environmental mixture of polycyclic aromatic hydrocarbons induces hepatic cytochrome P450 enzymes in mice

Stoddard, Ethan G.; Nag, Subhasree; Martin, Jude; Tyrrell, Kimberly J.; Gibbins, Teresa M.; Anderson, Kim A.; Shukla, Anil K.; Corley, Richard A.; Wright, Aaron T.; Smith, Jordan N.

doi:10.1021/acs.chemrestox.1c00235

Title: Exposure to an environmental mixture of polycyclic aromatic hydrocarbons induces hepatic cytochrome P450 enzymes in mice

Journal Article · Mon Sep 20 00:00:00 EDT 2021 · Chemical Research in Toxicology

DOI:https://doi.org/10.1021/acs.chemrestox.1c00235· OSTI ID:1827273

Stoddard, Ethan G. ^[1]; Nag, Subhasree ^[1]; Martin, Jude ^[2]; Tyrrell, Kimberly J. ^[1]; Gibbins, Teresa M. ^[1]; Anderson, Kim A. ^[3];

^[1]; Corley, Richard A. ^[1];

^[1]; Smith, Jordan N. ^[1]

BATTELLE (PACIFIC NW LAB)
HANFORD LABORATORY MGMT & INTEGRATION
Oregon State University

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 µmol/kg/d) of benzo[a]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 hr at the lowest PAH exposures and broad induction of many CYPs after 3 daily PAH doses at 72 hr following the first dose. Using samples displaying Cyp1a1 induction, we observed significantly higher metabolic affinity for BaP metabolism (Km reduced 3-fold), 3-fold higher intrinsic clearance, but no changes to the Vmax. Mice dosed with the highest PAH exposures exhibited 1.7 to 5-fold higher intrinsic clearance rates for BaP compared to controls and higher Vmax 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, and 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.

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Research Organization:: Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC05-76RL01830

OSTI ID:: 1827273

Report Number(s):: PNNL-SA-163871

Journal Information:: Chemical Research in Toxicology, Vol. 34, Issue 9

Country of Publication:: United States

Language:: English

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