posted on 2021-09-02, 11:37authored byEthan
G. Stoddard, Subhasree Nag, Jude Martin, Kimberly J. Tyrrell, Teresa Gibbins, Kim A. Anderson, Anil K. Shukla, Richard Corley, Aaron T. Wright, Jordan N. Smith
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 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 (Km reduced 3-fold),
3-fold higher intrinsic clearance, but no changes to the Vmax. Mice dosed with the highest PAH exposures exhibited
1.7–5-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, 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.