Redox homeostasis and stress in mouse livers lacking the NADPH-dependent disulfide reductase systems

Abstract

This thesis includes two reviews that cover the background of cellular disulfide reduction, from its earliest form in hydrothermal vents and its evolution to the current, multifaceted systems that maintain cellular redox homeostasis, to the roles of the disulfide reductase systems in different subcellular compartments, as well as provide a current status for many of the unkown roles disulfide reductase enzymes play. Furthermore, this thesis includes two published research articles, both relating changes in the NADPH-dependent disulfide reductase systems to altered physiology and the possible impacts of these changes to human health (ie cancer, acetaminophen overdose or toxic arsenic exposure.) A third research paper is also included in this thesis, which demonstrates the pro-oxidant effects of administration of the antioxidant ascorbate to TrxR1/Gsr-null livers. This paper is potentially valuable both in a clinical aspect, where ascorbate might be prescribed to counter the effects of excess oxidants, but also to the general public, as ascorbate is one of the most commonly taken over-the-counter supplements. The final chapter of this thesis is fundamental groundwork for future projects aimed at identifying how cells manage accumulation of oxidants/compromised disulfide reductase systems. The two isotopically labled amino acids, L-(^34 S)Met and L-(^34 S)cystine, are valuable tools to monitor S-metabolism, both in the TrxR1/Gsr-null livers but also in other disease states, such as those mentioned above. L-(^34 S)cystine is of particular interest to one of our collaborators, Dr. Gina DeNicola, who plans to use L-(^34 S)cystine to monitor S-metabolism in pancreatic organoids to study pancreatic adenocarcinoma.