Regulation glutathione synthesizing and regenerating enzymes by xenobiotics in the brain of mice with targeted deletion of the NRF2 transcription factor gene

Abstract

Basal expression of certain antioxidant enzymes was shown to be lower in the livers of Nrf2(-/-) mice (Hayes et al., 2000). In order to investigate the role of Nrf2 in the regulation of GSH synthesizing and regenerating enzymes in the brain, cytosols from the brains of Nrf2(-/-) mice treated with the antioxidant agents ethoxyquin, oltipraz, kahweol palmitate or indole-3-carbinol were analysed for glutathione content, expression and activity of certain antioxidant enzymes. The analysis enzyme activities indicated reduction of 6 phosphogluconate dehydrogenase and Glutathione reductase activities by almost 14 and 20% in Nrf2 null compared with the wild type control respectively. Treatment with chemopreventive agents increased the levels of these enzymes in Nrf2(-/-) mice brain. But only 6-phosphogluconate dehydrogenase activity was increase in both Nrf2(+/+) and Nrf2(-/-) mice brain. However, deletion of Nrf2 did not affect the protein levels of glutmyl cysteine ligase (GCL) and glutathione synthetase (GS) enzymes. Despite lack of apparent effect of the deficiency of Nrf2 on the levels of proteins of GCL and GS, upon treatment with chemical additives, there was an increase in the level of GSH in both Nrf2(+/+) and Nrf2(-/-) mice brain upon treatment with chemical additives. Keywords: Antioxidant, Beta zipper (bZip) transcription factors Glutamylcysteine Ligase , Glutamylcysteine Ligase Modifier subunit, Glutamylcysteine Ligase Catalytic subunit, Glutathione synthetase , Glutathione peroxidise1 Abbreviation: Nrf1, Nrf2