Reactive oxygen species, antioxidants, and the mammalian thioredoxin system

Reactive oxygen species (ROS) are known mediators of intracellular signalin g cascades. Excessive production of ROS may, however, lead to oxidative str ess, loss of cell function, and ultimately apoptosis or necrosis. A balance between oxidant and antioxidant intracellular systems is hence vital for c ell function, regulation, and adaptation to diverse growth conditions. Thio redoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquit ous oxidoreductase system with antioxidant and redox regulatory roles. In m ammals, extracellular forms of Trx also have cytokine-like effects. Mammali an TrxR has a highly reactive active site selenocysteine residue resulting in a profound reductive capacity, reducing several substrates in addition t o Trx. Due to the reactivity of TrxR, the enzyme is inhibited by many clini cally used electrophilic compounds including nitrosoureas, aurothioglucose, platinum compounds, and retinoic acid derivatives. The properties of TrxR in combination with the functions of Trx position this system at the core o f cellular thiol redox control and antioxidant defense. In this review, we focus on the reactions of the Trx system with ROS molecules and different c ellular antioxidant enzymes. We summarize the TrxR-catalyzed regeneration o f several antioxidant compounds, including ascorbic acid (vitamin C), selen ium-containing substances, lipoic acid, and ubiquinone (Q10). We also discu ss the general cellular effects of TrxR inhibition. Dinitrohalobenzenes con stitute a unique class of immunostimulatory TrxR inhibitors and we consider the immunomodulatory effects of dinitrohalobenzene compounds in view of th eir reactions with the Trx system. (C) 2001 Elsevier Science Inc.