Induction of Hepatic Glutathione S-Transferases in Male Mice by Prototypes of Various Classes of Microsomal Enzyme Inducers

Abstract

The underlying need for glutathione S-transferase (Gst) induction is thought to be an adaptive response to chemical stress within the cell. Classical microsomal enzyme inducers (MEIs) increase the expression of biotransformation enzymes (phase I and II) and transporters through transcription factors, such as the aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor (PPAR) alpha, and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). The effects of MEIs on the induction of hepatic Gsts in mice have not been comprehensively characterized. The purpose of this study was to determine the effects of 15 MEIs on the mRNA expression of 19 mouse Gsts. Male C57BL/6 mice were treated with three different activators each for AhR, CAR, PXR, PPARalpha, and Nrf2. In general, the Gsts are readily induced. All five transcription factors appear to play a role in Gst induction. The Nrf2 activators induced most Gsts (10), followed by the CAR, PXR, and PPARalpha activators (6-7), whereas the AhR ligands induced the least (1). Clofibrate, a PPARalpha agonist, induced most of the Gsts; however, all three PPARalpha agonists decreased Gstp1/2 mRNA. None of the 15 inducers was able to increase or only minimally increased eight of the Gsts (Gsta3, Gstk1, Gstm6, Gsto1, Gstp1/2, Gstt3, Gstz1, and MGst1). Thus, the protection afforded by a ligand for one of these transcription factors will depend on the activator, as well as which Gst that detoxifies the chemicals of interest.