Response of Cytoprotective and Detoxifying Proteins to Vanadate and/or Magnesium in the Rat Liver: The Nrf2-Keap1 System

Abstract

Oxidative stress (OS) is a mechanism underlying metal-induced toxicity. As a redox-active element, vanadium (V) can act as a strong prooxidant and generate OS at certain levels. It can also attenuate the antioxidant barrier and intensify lipid peroxidation (LPO). The prooxidant potential of V reflected in enhanced LPO, demonstrated by us previously in the rat liver, prompted us to analyze the response of the nuclear factor erythroid-derived 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2-Keap1) system involved in cellular regulation of OS to administration of sodium metavanadate (SMV, 0.125 mg V/mL) and/or magnesium sulfate (MS, 0.06 mg Mg/mL). The levels of some Nrf2-dependent cytoprotective and detoxifying proteins, i.e., glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), glutamate cysteine ligase catalytic subunit (GCLC), glutathione synthetase (GSS), NAD(P) H dehydrogenase quinone 1 (NQO1), UDP-glucumno-syltransferase 1 (UGT1), and heme oxygenase 1 (HO-1); glutathione (GSH); metallothionein (MT1); and glutamate-cysteine ligase (GCL) mRNA were measured. We also focused on the V-Mg interactive effects and trends toward interactive action as well as relationships between the examined indices. The elevated levels of Nrf2, GCL mRNA, and GCL catalytic subunit (GCLC) confirm OS in response to SMV and point to the capacity to synthesize GSH. The results also suggest a limitation of the second step in GSH synthesis reflected by the unchanged glutathione synthetase (GSS) and GSH levels. The positive correlations between certain cytoprotective/detoxifying proteins (which showed increasing trends during the SMV and/or MS administration, compared to the control) and between them and malondialdehyde (MDA), the hepatic V concentration/total content, and/or V dose (discussed by us previously) point to cooperation between the components of antioxidant defense in the conditions of the hepatic V accumulation and SMV-induced LPO intensification. The V-Mg interactive effect and trend are involved in changes in Nrf2 and UGT1, respectively. The p62 protein has to be determined in the context of potential inhibition of degradation of Keap1, which showed a visible upward trend, in comparison with the control. The impact of Mg on MT1 deserves further exploration.