Figure 3.

The source and clearance of ROS. (a) Three major origins of ROS. The sources of ROS can be roughly classified into three major categories: exogenous, endogenous, and transition metal ion-catalyzed. Exogenous sources of ROS can elicit radical chain reactions, contain/produce ROS, or stimulate enzymatic ROS production. Endogenous sources of ROS include the various enzymes that produce ROS as by-products or as signaling mediators or as antimicrobial agents during inflammation. Many of these enzymes can be activated by stimulation by cytokines and growth factors, such as NOX, LOX, XO, and MPO. Some CYPs are inducible and can be upregulated by environmental pollutants, dietary phytocompounds, or drugs. The transition metal ion-catalyzed Fenton-reaction produces highly reactive hydroxyl radical from hydrogen peroxide. (b) Layers of antioxidant defense. There are several layers of antioxidant defense. Basal level antioxidant defenses provide buffering capacity upon ROS challenge. Radical scavengers can directly quench ROS, and metal-chelating proteins can block ROS generation catalyzed by the Fenton or Fenton-like reactions. Further antioxidant capacity is provided by inducible antioxidant enzymes that are mostly under the regulation of Nrf2/ARE signaling (see Figure 4). ROS can oxidize the thiol group of amino acid residues leading to intermolecular or intramolecular disulfide bond formation. These disulfide bonds that are caused by oxidation can lead to structural/functional alteration of proteins. These disulfide bonds can be reduced by the glutathione system and the thioredoxin system allowing resumption of protein function. NADPH plays an indispensable role in the recycling of glutathione and thioredoxin, and therefore metabolic enzymes that are involved in NADPH generation also account for antioxidant defense.