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Title: Benzo[a]pyrene Induction of Glutathione S-transferases: An activity-based protein profiling investigation

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated from combustion of carbon-based matter. Upon ingestion, these molecules can be bioactivated by cytochrome P450 monooxygenases to oxidized toxic metabolites. Some of these metabolites are potent carcinogens that can form irreversible adducts with DNA and other biological macromolecules. Conjugative enzymes, such as glutathione S-transferases or UDP-glucuronosyltransferases, are responsible for the detoxification and/or facilitate the elimination of these carcinogens. While responses to PAH exposures have been extensively studied for the bioactivating cytochrome P450 enzymes, much less is known regarding the response of glutathione S-transferases in mammalian systems. In this study, we investigated the expression and activity responses of murine hepatic glutathione S-transferases to benzo[a]pyrene exposure using global proteomics and activity-based protein profiling for chemoproteomics, respectively. Using this approach, we identified several enzymes exhibiting increased activity including GSTA2, M1, M2, M4, M6, and P1. One enzyme, GSTA4, was found to be highly enzymatically repressed with increasing B[a]P dose. Activity responses of several of these enzymes were identified as being expression-independent when comparing global and activity-based datasets, possibly alluding to as of yet unknown regulatory post-translational mechanisms.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [1]
  1. BATTELLE (PACIFIC NW LAB)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1567052
Report Number(s):
PNNL-SA-137670
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 32; Journal Issue: 6
Country of Publication:
United States
Language:
English

Citation Formats

Stoddard, Ethan G., Killinger, Bryan J., Nag, Subhasree, Martin, Jude, Corley, Richard A., Smith, Jordan N., and Wright, Aaron T. Benzo[a]pyrene Induction of Glutathione S-transferases: An activity-based protein profiling investigation. United States: N. p., 2019. Web. doi:10.1021/acs.chemrestox.9b00069.
Stoddard, Ethan G., Killinger, Bryan J., Nag, Subhasree, Martin, Jude, Corley, Richard A., Smith, Jordan N., & Wright, Aaron T. Benzo[a]pyrene Induction of Glutathione S-transferases: An activity-based protein profiling investigation. United States. doi:10.1021/acs.chemrestox.9b00069.
Stoddard, Ethan G., Killinger, Bryan J., Nag, Subhasree, Martin, Jude, Corley, Richard A., Smith, Jordan N., and Wright, Aaron T. Mon . "Benzo[a]pyrene Induction of Glutathione S-transferases: An activity-based protein profiling investigation". United States. doi:10.1021/acs.chemrestox.9b00069.
@article{osti_1567052,
title = {Benzo[a]pyrene Induction of Glutathione S-transferases: An activity-based protein profiling investigation},
author = {Stoddard, Ethan G. and Killinger, Bryan J. and Nag, Subhasree and Martin, Jude and Corley, Richard A. and Smith, Jordan N. and Wright, Aaron T.},
abstractNote = {Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated from combustion of carbon-based matter. Upon ingestion, these molecules can be bioactivated by cytochrome P450 monooxygenases to oxidized toxic metabolites. Some of these metabolites are potent carcinogens that can form irreversible adducts with DNA and other biological macromolecules. Conjugative enzymes, such as glutathione S-transferases or UDP-glucuronosyltransferases, are responsible for the detoxification and/or facilitate the elimination of these carcinogens. While responses to PAH exposures have been extensively studied for the bioactivating cytochrome P450 enzymes, much less is known regarding the response of glutathione S-transferases in mammalian systems. In this study, we investigated the expression and activity responses of murine hepatic glutathione S-transferases to benzo[a]pyrene exposure using global proteomics and activity-based protein profiling for chemoproteomics, respectively. Using this approach, we identified several enzymes exhibiting increased activity including GSTA2, M1, M2, M4, M6, and P1. One enzyme, GSTA4, was found to be highly enzymatically repressed with increasing B[a]P dose. Activity responses of several of these enzymes were identified as being expression-independent when comparing global and activity-based datasets, possibly alluding to as of yet unknown regulatory post-translational mechanisms.},
doi = {10.1021/acs.chemrestox.9b00069},
journal = {Chemical Research in Toxicology},
number = 6,
volume = 32,
place = {United States},
year = {2019},
month = {6}
}