Mechanisms of induction of cytosolic and microsomal glutathione transferase (GST) genes by xenobiotics and pro-inflammatory agents

Abstract

Glutathione transferase (GST) isoezymes are encoded by three separate families of genes (designated cytosolic, microsomal and mitochondrial transferases), with distinct evolutionary origins, that provide mammalian species with protection against electrophiles and oxidative stressors in the environment. Members of the cytosolic class Alpha, Mu, Pi and Theta GST, and also certain microsomal transferases (MGST2 and MGST3), are up-regulated by a diverse spectrum of foreign compounds typified by phenobarbital, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, pregnenolone-16α-carbonitrile, 3-methylcholanthrene, 2,3,7,8-tetrachloro-dibenzo-p-dioxin, β-naphthoflavone, butylated hydroxyanisole, ethoxyquin, oltipraz, fumaric acid, sulforaphane, coumarin, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole, 12-O-tetradecanoylphorbol-13-acetate, dexamethasone and thiazolidinediones. Collectively, these compounds induce gene expression through the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), the aryl hydrocarbon receptor (AhR), NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ) and CAATT/enhancer binding protein (C/EBP) β. The microsomal T family includes 5-lipoxygenase activating protein (FLAP), leukotriene C₄ synthase (LTC4S) and prostaglandin E₂ synthase (PGES-1), and these are up-regulated by tumour necrosis factor-α, lipopolysaccharide and transforming growth factor-β. Induction of genes encoding FLAP, LTC4S and PGES-1 is mediated by the transcription factors C/EBPα, C/EBPδ, C/EBPϵ, nuclear factor-κB and early growth response-1. In this article we have reviewed the literature describing the mechanisms by which cytosolic and microsomal GST are up-regulated by xenobiotics, drugs, cytokines and endotoxin. We discuss cross-talk between the different induction mechanisms, and have employed bioinformatics to identify cis-elements in the upstream regions of GST genes to which the various transcription factors mentioned above may be recruited.

Keywords::

• ARE (Antioxidant Response Element)
• tBHQ (tert-butylhydroquinone)
• CAR (Constitutive Androstane Receptor)
• Chemoprevention
• EpRE (Electrophile Response Element)
• GPEI (Glutathione transferase P Enhancer I)
• GRE (Glucocorticoid Response Element)
• GSH (reduced glutathione)
• Keap1 (Kelch-like ECH-associated protein 1)
• PBREM (Phenobarbital-Responsive Enhancer Module)
• XRE (Xenobiotic Response Element)
• Nrf2 (NF-E2-related factor 2)
• AhR (Aryl hydrocarbon Receptor)

Acknowledgements

We are most grateful to Dr Anatoly Saprin for translating the paper by Franfurt et al (1967) from Russian into English. LGH thanks Breast Cancer Campaign (grant no. 2007NovPR31) for support, and JDH thanks Cancer Research-UK for funding our work on Nrf2 (C4909/A9990). Whilst preparing this review, we greatly appreciated helpful comments from Richard N. Armstrong, Philip G. Board, Ralf Morgenstern and Russell A. Prough.

Declaration of interest

Neither LGH nor JDH declare any conflict of interest.